Substituted phenyl 2-piperidinocycloalkyl ketones

ABSTRACT

KETONES OF THE FORMULA III   ((-CH(-N&lt;(-Z-))-CH2-(CH2)N-)&gt;CH-CO-),R&#39;&#39;,R&#34;,R&#34;&#39;&#39;-BENZENE   WHEREIN N HAS THE VALUE 1 TO 4 INCLUSIVE,   -N&lt;(-Z-)   IS A HETEROCYCLIC AMINO RADICAL CONTAINING FROM 5 TO 10 NUCLEAR ATOMS, INCLUSIVE, AND WHEREIN R&#39;&#39;,R&#34; AND R&#34; ARE HYDROGEN, HALOGEN, ALKYL AND ALKOXY OF 1 TO 6 CARBON ATOMS, INCLUSIVE AND -CF3, WITH AT LEAST ONE OF THE VARIANT R&#39;&#39;, R&#34; BEING HALOGEN, ALKOXYL OR CF3 AND ACID ADDITION SALT ARE PREPARED. THE NEW KETONES ARE INTERMEDIATES FOR THE PRODUCTION OF THE CORRESPONDING 1,3-AMINOALCOHOLS AND ESTERS AND ETHERS THEREOF, WHICH HAVE DIURETIC AND SOMETIMES STRONG ANTI-HYPERGLYCEMIC ACTIVITY AND ARE THUS USEFUL TO PROMOTE DIURESIS IN MAMMALS OR AS ORAL ANTIDIABETIC AGENTS.

3,632,813 SUBSTITUTED PHENYIL Z-PIIPERIDlNOCYCLO- ALKYL KETONES JacobSzmnszkovicz, Kalamazoo, Mich, assignor to The Upjohn Company,Kalamazoo, Mich.

No Drawing. @riginal application June 13, 1966, Ser. No. 556,892, nowPatent No. 3,558,599. Divided and this application Dec. 23, 1968, Ser.No. 786,421

lint. Ql. (307d 29/20 US. Cl. 260-2945 I 4 Claims ABSTRACT OF THEDISCLOSURE Ketones of the Formula III (Clint, R

1 RI! b l1 I O /I/ N R Z III wherein n has the value 1 to 4 inclusive,

is a heterocyclic amino radical containing from 5 to nuclear atoms,inclusive, and wherein R, R and R are hydrogen, halogen, alkyl andalkoxy of 1 to 6 carbon atoms, inclusive and -CF with at least one ofthe variant R, R and R' being halogen, alkoxy or CF and acid additionsalt are prepared. The new ketones are intermediates for the productionof the corresponding 1,3-aminoalcohols and esters and ethers thereof,which have diuretic and sometimes strong anti-hyperglycemic activity andare thus useful to promote diuresis in mammals or as oral antidiabeticagents.

ted States Pate wherein n has the value of l to 4, inclusive, wherein zk) represents a heterocyclic amino radical containing from 5 to 10nuclear atoms, inclusive, wherein R is an alkyl containing from 1 to 6carbon atoms, inclusive, wherein R, R, R' are selected from the group ofsubstituents consisting of hydrogen, halogen, alkyl and alkoXycontaining from 1 to 6 carbon atoms, inclusive, and -CF and wherein Acis the acyl radical of a hydrocarbon carboxylic acid containing from 2to 12 carbon atoms, inelusive.

The invention further includes the compounds of Formulae IV, IVa and IVbwhen in the form of the N- oxides, acid addition salts and quaternaryalkyl ammonium halides in which the alkyl group has from 1 to 12 carbonatoms, inclusive, and the halogen can be chlorine, bromine and iodine.Also the acid addition salts of the compounds of Formula III areembraced by this invention.

Examples of the cycloalkyl radical illustratively represented by theformula DPI are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Examples of the heterocyclic amino radical having from 5 to 10 nuclearatoms, include: pyrrolidino, Z-methylpyrrolidino, 2-ethylpyrrolidino,2,2-dimethylpyrrolidino, 3,4-dimethylpyrrolidino,2-isopropylpyrrolidino, 2-sec.butylpyrrolidino, and like:alkylpyrrolidino groups, morpholino, 2-ethylrnorpholino,2-ethyl-5-rnethylmorpholino, 3,3-dimethylmorpholino, thiamorpholino,3-methylthiamorpholino, 2,3-trimethylthiamorpholino, 4-methylpiperazino,4-butylpiperazino, piperidino, Z-methylpiperidino, 3-methylpiperidino,4-methlpiperidino, 4-propylpiperidino, 2-propylpiperidino,4-isopropylpiperidino, and like alkylpiperidino groups,hexamethyleneimino, 2- methylhexamethyleneimino,3,6-dimethylhexamethyleneimino, homomorpholino,1,2,3-tetrahydroquinolyl, heptamethyleneimino, octamethyleneimino,3-azabicyclo- [3.2.2]nonan-3-y1, 2-azabicyclo[2.2.2]octan-2-yl, and thelike.

Illustrative examples of alkyl groups having from 1 to 6 carbon atomsare methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,pentyl, 2 -methylbutyl, neopentyl, hexyl, Z-methylpentyl, 3-methylpentyland the like. Alkyl groups for the quaternary ammonium halide saltsinclude, in addition to the preceding alkyl groups, others such asheptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The halogenmoiety in such salts includes iodine, bromine and chlorine.

Illustrative examples of the acyl groups Ac of hydrocarbon carboxylicacids are particularly the acyl groups of alkanoic acids of 2 to 12carbon atoms, e.'g., acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, hexanoyl, octanoyl, decanoyl, [i-cyclopentylpropionyl,lauroyl; of benzoic and aralkanoic acids, e.g., benzoyl, phenylacetyl,3-phenylpropionyl, toluoyl, ethylbenzoyl, propylbenzoyl; of alkenoicacids, e.g., acryloyl, crotonoyl, chrysanthemummonocarbon-yl, cinnamoyl,hexenoyl; of alkynoic acids, e.g., propiooyl, 2- and 3-butynoyl and thelike.

Under halogen substitutents for R, R or R is understood fluorine,chlorine, bromine and iodine.

The novel compounds III, IV, We and Nb exist in different stercoisomericforms such as geometric and optically active forms (e.g., compounds ofFormula III have at least two asymmetric carbon atoms, while the finalproducts, IV, We and IVb, have at least three asymmetric carbon atoms)as well as in racemic mixtures. These optically active forms and racemicmixtures and geometric isomers are also encompassed by this invention.

The process of the present invention comprises: heating a diketocompound of Formula I in which one of the radicals on the centralcarbonyl group is a 2-oxocycloalkyl group having from 5 to 8 carbonatoms, inclusive, and the other group is substituted or unsubstitutedphenyl, with a heterocyclic amine KW H-N Z having from 5 to 10 nuclearatoms, inclusive, in the presence of an acidic catalyst, e.g.,p-toluenesulfonic acid, to give the unsaturated keto compound of FormulaII; hydrogenating the thus-obtained compound II in the presence of ahydrogenation catalyst, preferably a noble metal catalyst such asplatinum oxide, rhodium, palladium or the like to add stepwise one andthereupon two molar equivalents of hydrogen, thus yielding respectively(with 1 molar equivalent of hydrogen) the keto compound III and (with 2molar equivalents of hydrogen) the alcohol IV. The thus-obtained1,3-amino alcohols IV can be converted to alcohol derivatives such asesters (IVa) with an alkyl halide (1 to 6 carbon atoms) in the presenceof a base, or with a lower alkanol (l to 6 carbon atoms) in the presenceof anhydrous hydrogen chloride, and to esters (IVb) with an acidanhydride or acid halide in a suitable organic solvent.

The amino function in Formulae 1V, IVa and IVb compounds furthermorepermits the transformation of these compounds, by neutralization withinorganic and organic acids, into acid addition salts such as thehydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,perchlorate, pamoate, cyclohexane-sulfamate, methanesulfonate,ethanesulfonate, p-toluenesulfonate, benzenesulfonate, tartrate,citrate, lactate, and the like. By treatment of the compounds ofFormulae IV, IVa and Nb with peracids such as m-chloroperbenzoic acid,peracetic acid, perbenzoic acid, perphthalic acid, and the like, thecorresponding N-oxide derivatives are obtained. By treatment of thecompounds of Formulae IV, IVa and Nb with alkyl halides, thecorresponding quaternary ammonium halide salts are obtained.

The compounds of Formulae IV, Na, and Nb, including the acid additionsalts, the N-oxides, and the alkyl quaternary ammonium halides thereof,are compounds of significant diuretic activity. They may be administeredto mammals and birds by both oral and parenteral routes in order toproduce their pharmacological, that is, diuretic effects. For oraladministration, the new compounds of Formulae IV, IVa and Nb, as well asthe acid addition salts, the N-oxides and the quaternary ammonium halidesalts, can be compounded into solid and liquid unit dosage forms such astablets, capsules, powders, granules, syrups, elixirs and the like,containing the appropriate amounts for treatment. For tablets, commonpharmaceutically acceptable carriers are used such as starch, lactose,kaolin, dicalcium phosphate and the like. The compounds IV, IVa and IVbcan also be given as powders, particularly in gelatin capsules with orwithout carriers such as methylcellulose, magnesium stearate, calciumstearate, talc and the like. For fluid preparations, these compounds maybe dissolved or suspended in aqueous alcoholic vehicles with or withoutbuffering agents and flavoring mixtures.

The thus-obtained pharmaceutical formulations are administered toedematous animals for the treatment of conditions associated with excesselectrolyte retention and excess fluid retention. For example, thecompositions are useful in treating the following conditions: edemaassociated with hepatic disease, edema and toxemia of pregnancy,hypertensive vascular disease, premenstrual fluid retention andcongestive heart failure. Dosages between 0.5 and 30 mg./kg. of bodyweight are suitable to produce significantly increased diuresis. Forexample, the ether cis- 1- [2- a,p-dimethoxybenzyl) cyclohexyl]-piperidine of melting point 8385 C. produced at 5 mg. dosage level perkg. of body weight of rats at 73% increase in diuresis, as determined bythe procedure of Lipschitz et al., J. Pharmacol. Exp. Therap. 79, 97,1943.

The compounds of Examples 38, 39, 48, 54, 55, 97, 99, and 136A havedemonstrated significant anti-hyperglycemic activity in rats. They areuseful as oral antidiabetic agents.

As noted above, the new compounds of Formulae 1V, IVa and Nb can be usedin the form of their acid addition salts with inorganic or organicacids, for example, hydrochlorides, lactates, sulfates, tartrates,hydroiodides, hydrobromides, and the like. Moreover, the fluosilicatesof these compounds are useful moth-proofing agents according to US.Pats. 1,915,334 and 2,075,359. The thiocyanic acid addition salts of thesame compounds can be condensed with formaldehyde to form resinouspolymers which according to US. Pats. 2,425,320 and 2,606,155 are usefulas pickling inhibitors. The trichloroacetic acid addition salts of thecompounds of the same formulae IV, IVa and Nb are useful as herbicides,for example, against Johnson grass, yellow foxtail, green foxtail,Bermuda grass and quack grass.

The alkyl quaternary ammonium halides of the compounds of Formulae IV,Na and Nb, such as a.-(3,4,5-trimethoxyphenyl) 2(hexahydro-l-methyl-l-azepinium) cyclohexanemethanol iodide (Example142), possess high wetting power and electroconductivity and are thussuitable to prepare electrocardiographic jellies.

A suitable composition of an electrocardiographic jelly thus preparedcomprises:

Parts Glycerol 5 Starch 10 Quaternary ammonium salt 60 Water 100 Thejelly is prepared by mixing the starch, glycerol and water and thenadding the quaternary ammonium salt. The mixture is then allowed tostand for at least two days with occasional agitation to allow theformation of a gel.

The starting materials of Formula I are known in part from the art,e.g., Campbell et al., I. Am. Chem. Soc. 82, 2389, (1960); Linn et al.,J. Am. Chem. Soc. 78, 6066 (1 956); Eistert et al., Ann. 650, 133(1961). An elegant method by which the 1,3-diones of the type of FormulaI are synthesized consists of the reaction of a selected cycloalkanonewith pyrrolidine or piperidine to give the corresponding enamine and toreact the enamine with a selected substituted or unsubstituted benzoylchloride [Campbell et al., J. Org. Chem. 28, 379 (1963)]. Thisparticular method is shown repeatedly in the examples in order tosynthesize hitherto unknown 1,3-diones of the type of Formula I.

In carrying out the process of the present invention a 1,3-diketocompound (I) is reacted with a heterocyclic amine in the presence of aacid catalyst and preferably under conditions in which the waterproduced in the condensation process is separated from the reactionmixture such as by employing an azeotropic separator together With thereflux condenser. As solvent, essentially waterfree organic solvents areused such as benzene, toluene, xylene or the like. The heterocyclicamines used include particularly pyrrolidine, Z-methylpyrrolidine,2-ethylpyrrolidine, 2,2-dimethylpyrrolidine, 3,4-dimethylpyrrolidine,2-isopropylpyrrolidine, 2-sec.butylpyrrolidine and other likealkylpyrrolidines; morpholine, 2-ethylmorpholine, 2-ethyl-S-methylmorpholine, 3,3-dimethylmorpholine, thiamorpholine,3-methylthiamorpholine, 2,3,6trimethylthia-. morpholines and other likealkylmorpholines and alkylthiamorpholines; 4 methylpiperazine, 4-butylpiperazine and other like alkylpiperazines; piperidine,Z-methylpiperidine, 3 methylpiperidine, 4 methylpiperidine, 4-propylpiperidine, Z-propylpi-peridine, 4-isopropylpiperidine and otherlike alkylpiperidines; hexamethyleneimine, 2- methylhexamethyleneimine,3,6 dimethylhexamethyleneimine and other like alkylhexamethyleneirnines;homomorpholine, 1,2,3,4-tetrahydroquinoline, heptamethyleneimine,octamethyleneimine, 3-azabicyclo[3.2.2]nonane, 2-azabicyclo[2.2.2]octane, and the like.

The reaction is generally carried out at temperatures between 50-150 C.but lower or higher temperatures are operative. Preferably, the reactionis carried out at the reflux temperature of the reaction mixture. Thetime for completion of the reaction is between 1 hour and 48 hours, butif low temperatures are used, longer reaction times are necessary. Whenthe reaction is terminated, the product is isolated in conventionalmanner such as evaporating the reaction mixture to dryness.

The keto product of Formula II is then hydrogenated in the presence of acatalyst, preferably platinum oxide, at a hydrogen pressure between 40and 60 pounds per square inch. Larger or smaller pressures can be used,but pressures between 50-55 pounds at the beginning of the reaction arefound to be most convenient. The reaction can be followed by thehydrogen absorption and can be allowed to go to completion, that is, tothe point of addition of 2 molar equivalents of hydrogen to give thealcohol of Formula IV, or alternatively may be interrupted after theadidtion of 1 molar equivalent of hydrogen to give the keto compound ofFormula III. -In cases where the addition of hydrogen is slow,additional amounts of catalyst may be added after an interval of severalhours. Other catalysts that can be used in this reaction are palladiumand rhodium, and these catalysts can be used with catalyst carriers suchas charcoal, alumina and the like. After the hydrogenation is completed,the product is isolated by filtering the mixture to remove the catalystand evaporating the solvent to obain either the keo compound of FormulaIII or the alcohol of Formula IV. The thusisolated products are purifiedby conventional means such as by crystallization and recrystallization,chromatography, or the like. If desired, the keto product of Formula IIIcan be hydrogenated again to give the alcohol of Formula IV.

The conversion of the alcohol of Formula IV to an ether of Formula IVais usually achieved by two methods: 1) reacting the alcohol of FormulaIV in liquid ammonia containing sodium amide or potassium amide at lowtemperature with the selected alkyl halide, or (2) reacting the alcoholof Formula IV with a lower alkanol in the presence of hydrogen chloride.The starting temperature of the first method is usually the temperatureof a Dry Ice-acetone bath, that is, approximately 70 C. and is completedat about room temperature. In the preferred embodiment of thisinvention, the selected alcohol (IV), is dissolved in ether and is addedto liquid ammonia containing sodium amide under continuous stirring.When this mixture reaches the Dry Ice-acetone bath temperature, asolution of the alkyl halide, preferably an alkyl iodide, is added over.a few minutes time to allow cooling. When the calculated amount ofalkyl halide is consumed, the reaction mixture in the flask is removedfrom the Dry Ice-acetone bath and allowed to warm to room temperatureunder continuous stirring. Instead of sodium amide, other strong basiccompounds can be used such as potassium amide, lithium amide, and thelike. Instead of liquid ammonia and alkali metal amides, other reactionsystems can be used, e.g., butyl lithium in the presence oftetrahydrofuran and a temperature range of about 70 to 25 C. After thereaction is terminated, the ether thus produced (IVa) is isolated byconventional procedures such as extraction, evaporation of solvents,formation of amine addition salts such as the hydrochloride, and usingthe differential water solubility of the hydrochloride and the like. Forpurification,

recrystallization and chromatography, are usualy employed.

In the second method, the alcohol IV is stirred with a solution ofhydrogen chloride gas in a lower alkanol, e.g., methanol, ethanol,propanol, l-butanol, Z-butanol and the like, usually at roomtemperature. Lower or higher temperatures are operative, however. Theproduct is ob tained as a hydrochloride of the: amino ether. The freebase is obtained by treating the hydrochloride with a base, e.g., 20%aqueous sodium hydroxide, extracting the free base with awater-immiscible solvent, e.g., ether, methylene chloride, chloroformand the like and evaporating the solvent.

Esters (IVb) of the alcohol of Formula IV are usually, obtained inconventional manner, that is, treatment of the alcohol with an acidanhydride or acid halide, preferably in solution at room temperature.The solvents used in this reaction are methylene chloride,tetrahydrofuran, pyridine and the like. The anhydrides used in thisreaction are usually of hydrocarbon carboxylic acids, e.g., of alkanoicacids such as acetic, propionic, butyric, isobutyric, valeric, hexanoic,heptan-oic, octanoic acids and the like; of benzoic and aralkanoic acidssuch as benzoic acid, salicyclic acid, toluic acid, phenylacetic acid,3-phenylpropionic acid and the like; of cycloalkanoic acids, e.g., ofcyclohexanecarboxylic acid and the like. The acid halides used in thisreaction can be of alkanoic acids, particularly higher alkanoic acidshaving from 6 to 12 carbon atoms, such as hexanoyl chloride, heptanoylchloride, octanoyl chloride, decanoyl chloride, undecanoyl chloride,lauroyl chloride or the acid bromides thereof, but the chlorides andbromides of lower alkanoic acids are. also useful. The invention alsoencompasses the use of the anhydrides and acid chlorides and bromides ofunsaturated acids such as cinnamic acid, acrylic acid, crotonic acid,propiolic acid, 2- butynoic acid, chrystanthemummonocarboxylic acid andthe like. After termination of the reaction, the product is isolated byconventional procedures such as extraction, chromatography,crystallization and the like.

Acid addition salts of the amino alcohols (IV), amino ethers (IVa) andamino esters (IVb) are synthesized in the usual manner, that is, bydirectly reacting the acid with the free amine, preferably in an aqueousor anhydrous solvent such as water, ether, methanol, ethanol, ethylacetate or the like. Evaporation of the solvent provides the desiredacid addition salt.

N-oxides of the compounds of Formulae IV, IVa and IVb are obtained byreacting the compound at a temperature between 030 C., preferably at thestart of the reaction at a temperature between 0l0 C., with a peracidsuch as peracetic, perpropionic, perbenzoic, perphthalic,m-chloroperbenzoic or other organic peracids in a solvent such asmethanol, ethanol, ether or the like. Evaporation of the solventprovides the desired N-oxide of the products of Formulae IV, Na and IVb.

The alkyl quaternary ammonium halides of products of Formulae IV, IVaand Nb are produced by conventional methods such as heating to reflux asolution of the selected compound IV, IVa or IVb in the presence ofmethanol, ethanol, acetonitrile or the like with a selected alkyl halidesuch as an iodide or bromide or, less desirably, a chloride of methyl,ethyl, propyl, butyl, isobutyl, isopropyl, pentyl, hexyl, heptyl, octyl,decyl, undecyl, dodecyl or isomers of these alkyl compounds. After thereaction is terminated, the reaction mixture is evaporated to dryness togive the product which can be purified by recrystallization from organicsolvents such as methanol, ethanol, ether, Skellysolve B hexane,mixtures thereof and the like.

It is obvious from the configuration of products III, IV, IVa and IVbthat these products can exist in more than one isomeric structure, sincethe compounds of Formula III have at least two asymmetric centers andthose of Formula IV, IVa and IVb have at least three asymmetric centers,as noted above. It will be seen from the examples that many of thereactions are either stereospecific giving only one single product(racemic) or are stereo-selective, that is, giving one major componentwith smaller amounts of other components. Thus, the hydrogenation of thecompound II to the ketone III with platinum oxide appears to give onlyone single form of the cis-ketone. Heating the thus-obtained cis-ketonewith a base, for example, refluxing it with piperidine, produces asingle trans-ketone III, which according to thermodynamic principles ofstability has the substituents on the cycloalkane moiety in theequatorial position.

Further hydrogenation of a cis-ketone of Formula III with platinum oxideas catalyst products one single cisalcohol form (racemate A). Heatingthis cis-alcohol of Formula IV with trifluoroacetic acid producesanother Formula IV cis-alcohol (racemate B).

Further hydrogenation of a trans-ketone of Formula III with platinumoxide as catalyst produces one single Formula IV trans-alcohol (racemateC) which can be converted to the other Formula IV trans-alcohol(racemate D) with trifluoroacetic acid. Reduction of a transketone ofFormula III with lithium aluminum hydride produces the twoabove-mentioned trans-alcohols of Formula IV. The racemates can beresolved by standard methods. The subsequent examples further illustratethe stereo-isomeric considerations.

The following examples are illustrative of the process and the productsof the present invention, but are not to be construed as limiting.

EXAMPLE 1 2- 3,4,5 -trimethxybenzoyl) cycl 0h exanone A mixture of 147g. (1.5 moles) of cyclohexanone and 213.3 g. (3 moles) of pyrrolidinewas refluxed in 2250 m1. of benzene in a flask equipped with anazeotropic separator. After the water formed during the reaction wascollected, the solution was evaporated to dryness in vacuo and theresulting crude oil, consisting of l-pyrrolidino-l-cyclohexene, was useddirectly for the next step.

A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g.; 0.6 mole) in240 ml. of chloroform was added during a period of 2 hours to a solutionof the crude l-pyrrolidino-l-cyclohexene in 630 ml. of chloroform, undera nitrogen atmosphere, with continuous stirring while keeping thetemperature between 5 to C. After the solution was stirred overnight(about 18 hours) at room temperature (about 22 to 25 C.), there wasadded 900 ml. of 10% aqueous hydrochloric acid, and the resultingmixture was stirred at room temperature for 2 hours. The aqueous layerwas extracted with two 150-ml. portions of chloroform, and thechloroform extracts were combined with the chloroform layer above. Thecombined extracts were washed with water, saturated aqueous sodiumbicarbonate solution, water and saturated salt solution. Thethus-obtained chloroform solution was dried by passing it throughanhydrous sodium sulfate and the dry solution was evaporated to give aresidue which was crystallized from methanol to yield 100 g. of long,colorless needles of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone of meltingpoint l4l142 C.

Analysis.Calcd. for C H O (percent): C, 65.74; H, 6.90. Found (percent):C, 65.48; H, 6.84.

EXAMPLE 2 2-(3,4,5-trimeth0xybenzoyl) cyclopentanone A mixture of 126 g.(1.5 moles) of cyclopentanone and 213.3 g. (3 moles) of pyrrolidine wasrefluxed in 2250 ml. of benzene in a flask equipped with an azeotropicseparator. After the calculated amount of water, produced during thecondensation, had been collected, the reaction mixture was evaporated togive as an oil l-pyrrolidino-l-cyclopentene.

A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g.; 0.6 mole) inchloroform was added to a chloroform solution of the oily1-pyrrolidino-l-cyclopentene over a period of 1 hour. The reactionmixture was thereupon worked up as in Example 1 to give a brown oilweighing 190 g. This oil was dissolved in 500 ml. of ethanol and theethanol solution was added to a solution of 172 g. of cupric acetatemonohydrate in 2600 ml. of water. The mixture was stirred for /2 hour,cooled and filtered, providing a crude copper complex of2-(3,4,5-trimeth0xybenzoyl)cyclopentanone. This product was crystallizedfrom methylene chloride to give g. of the pure copper complex melting at206208 C.

Analysis.Calcd. for C H CuO (percent): C, 58.29; H, 5.54; Cu, 10.28.Found (percent): C, 58.58; H, 5.81; Cu, 9.49.

The thus-obtained copper complex (70 g.) was dissolved in 350 ml. ofchloroform and decomposed with 670 ml. of 10% aqueous hydrochloric acidto give 60 g. (yield 36%) of 2-(3,4,5-trimethoxybenzoyl)cyclopentanonehaving a melting point of 8186 C. A sample of this material wasrecrystallized from Skellysolve B hexanes to give 2-(3,4,5-trimethoxybenzoyl)cyclopentanone of melting point 92 95 C.

Analysis.Calcd. for C H O (percent): C, 64.74; H, 6.52. Found (percent):C, 64.95; H, 6.52.

In a run twice the size of the above synthesis, a yield of 47% wasobtained.

EXAMPLE 3 2-(3,4,5-trimethoxybenzoyl) cycloheptanone A mixture of 500 g.of cycloheptanone (4.5 moles), 785 g. of morpholine (9 moles), 900 ml.of toluene and 5 g. of ptoluene-sulfonic acid was refluxed for 23 hours,collecting the water produced in the reaction with an azeotropicseparator. Ninety-eight ml. of a lower phase was collected anddiscarded. The remaining mixture was then evaporated in vacuo to give anoil which was distilled. The fraction boiling between 119-125 C.consisted essentially of 262.7 g. of l-morpholino-l-cycloheptene (32%yield).

In the manner given in Example 1, 3,4,5-trimethoxybenzoyl chloride (92.5g.; 0.4 mole) was reacted with 181.37 g. (1 mole) ofl-morpholino-l-cycloheptene. The crude product was crystallized from 500ml. of methanol and gave a first crop of 26 g. of2-(3,4,5-trimethoxybenzoyl)cycloheptanone of melting point 99-100" C.After two more recrystallizations from methanol, the product had amelting point of 107108 C.

Analysis.-Calcd. for C H O (percent): C, 66.65; H, 7.24. Found(percent): C, 66.16; H, 7.48.

From the above methanolic filtrate another 48.3 g. of 2-( 3,4,5-trimethoxybenzoyl)cycloheptanone was obtained as a second crop. Thetotal yield was 61%.

EXAMPLE 4 2- (p-methoxybenzoyl) cyclohexanone A solution of 167 g. (0.98mole) of p-anisoyl chloride in 480 ml. of chloroform was added during aperiod of 1.5 hours to a solution of 371.7 g. (2.46 moles) of distilled1- pyrrolidino-l-cyclohexene in 1260 ml. of chloroform. The temperaturewas kept between 510 C. by cooling with ice. After stirring for a periodof about 20 hours at room temperature, the mixture was decomposed byaddition of 1800 ml. of 10% aqueous hydrochloric acid over a period of20 minutes. The mixture was then stirred for 2 hours, allowed to settle,the organic layer was separated and the aqueous layer extracted twicewith 250-ml. portions of chloroform. The original organic layer and thechloroform extracts were combined, washed with water, saturated saltsolution, and then dried by passage through sodium sulfate andevaporated. The residue resulting from the above evaporation was a brownoil which was dissolved in 1 l. of ethanol and added to a solution of344 g. of cupric acetate monohydrate in 5200 ml. of water, preheated to65 C. The mixture was stirred for 0.5 hour, cooled to room temperatureand filtered. The obtained precipitate was washed with water and thenwith ether. It was then dissolved in 800 ml. of chloroform and added toa solution of 300 ml. of concentrated hydrochloric acid in 1100 ml. ofwater. The mixture was stirred for 1 hour. The organic layer wasseparated, and the aqueous layer was extracted once with chloroform. Thecombined chloroform original layer and extract were washed with water,saturated salt solution, dried by passing through anhydrous sodiumsulfate and evaporated, to give a solid which was crystallized from 7 l.of methanol, yielding 13 6.5 g. of 2- (p-methoxybenzoyl)cyclohexanonehaving a melting point of 115- 128 C. A second crop of 26 g., meltingpoint 116127 C., was obtained from the mother liquor; the total yieldwas 71%. A recrystallized sample from methanol of2-(p-methoxybenzoyl)cyclohexanone had a melting point of 117- 122 C.

Analysis.--Calcd. for C H O (percent): C, 72.39; H, 6.94. Found(percent): C, 72.30; H, 7.05.

EXAMPLE 5 2- (p-metlzoxybenzoyl cyclopent anone In the manner given inExample 2, 204 g. (1.2 moles) of p-anisoyl chloride was reacted withl-pyrrolidino-lcyclopentene prepared from 252 g. (3 moles) ofcyclopentanone. The crude product was converted to the copper complex asin Example 4, the complex being crystallized from chloroform-ether togive 80 g. of copper complex of Z-(p-methoxybenzoyl)cyclopentanone witha melting point of 252 C. (dec.). The copper complex was decomposed withhydrochloric acid to give 67 g. of an oil which was crystallized frommethanol to give 13.9 g. of 2-(p-methoxy benzoyl)cyclopentanone ofmelting point 82-83 C. The filtrate from the first crystallization wasevaporated to dryness and the residue crystallized fromether-Skellysolve B hexanes to give 30.1 g. of a second crop of2-(pmethoxybenzoyl)cyclopentanone of melting point 76- 77 C. (totalyield 17%). Two recrystallizations from methanol gaveZ-(p-methoxybenzoyl)cyclopentanone having a melting point of 8387 C.

Analysis.-Calcd. for C H O (percent): C, 71.54; H, 6.47. Found(percent): C, 71.83; H, 6.48.

EXAMPLE 6 2-(p-ethoxybenzoyl)cyclohexanone In the manner given inExample 2, l-piperidino'lcyclohexene was reacted with p-ethoxybenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(p-ethoxybenzoyl) cyclohexanone.

EXAMPLE 7 2- (p-benzyloxybenzoyl cyclohexanone In the manner given inExample 2, l-pyrrolidino-lcyclohexene was reacted withp-benzyloxybenzoyl chloride in chloroform solution to give, after thecopper complex purification procedure (Example 2),2-(p-benzyloxybenzoyl)cyclohexanone of melting point 1ll-111.5 C.

EXAMPLE 8 2- [p- (Z-hydroxyethoxy benzoyl 1 cyclohexanone In the mannergiven in Example 2, l-piperidino-lcyclohexene was reacted withp-(Z-acetoxyethoxy)benzoyl chloride in chloroform solution to give,after the copper complex purification procedure (Example 2), 2-[p-(2-acetoxyethoxy)benzoyl]cyclohexanone. The 2-[p 2acetoxyethoxy)benzoyl]cyclohexanone was subjected to alkaline hydrolysisin conventional manner, neutralized with acid and 2-[p-(2hydroxyethoxy)benzoyl1cyclohexanone recovered by extraction.

1Q i EXAMPLE 9 2- o-methoxybenzoyl cycl 0/1 era/Ion e In the mannergiven in Example 2, 1-piperidino-lcyclohexene was reacted witho-methoxybenzoyl chloride in chloroform solution to give, after thecopper complex purification procedure (Example 2), 2-(0methoxybenzoyl)cyclohexanone of melting point 65-68 C.

EXAMPLE 10 2- (o-lzydroxybenzoyl cyclohexanone In the manner given inExample 2, l-piperidino-1cyclohexene was reacted with o-acetoxybenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(o-acetoxybenzoyl)cyclohexanone.The thus-obtained 2-(o-acetoxybenzoyl)cyclohexanone was subjected toalkaline hydrolysis, the mixture acidified and the2-(o-hydroxybenzoyl)cyclohexanone recovered by extraction.

EXAMPLE 1 1 2- (Z-meth0xy4-methylbenz0yl) cyclohexanone In the mannergiven in Example 2, I-piperidino-lcyclohexene was reacted with2-methoxy-4-methylbenzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2), 2 (2-methoxy-4-methylbenzoyl)cyclohexanone.

EXAMPLE l2 2- (p-melhoxybenzoyl -4,4-dimethylcyclolzexanone In themanner given in Example 2, 1-piperidino-4,4- dimethyl-l-cyclohexene wasreacted with p-methoxybenzoyl chloride in chloroform solution to give,after copper complex purification procedure (Example 2), 2-(p-methoxybenzoyl)-4,4-dimethylcyclohexanone.

EXAMPLE 13 2-(3,5-dimethyl-4-methoxybenzoyl) cyclohexanone In the mannergiven in Example 2, l-pyrrolidino-lcyclohexene was reacted with3,5dimethyl 4 methoxy benzoyl chloride in chloroform solution to give,after the copper complex purification procedure (Example 2), 2-(3,5-dimethyl-4-methoxybenzoyl) cyclohexanone of melting point l26 C.

EXAMPLE 14 2- [p-(methylcarbamoyloxy benzoyl] cyclohexanone In themanner given in Example 2, l-piperidino-1- cyclohexene was reacted withp-methylcarbamoyloxybenzoyl chloride in chloroform solution to give,after the copper complex purification procedure (Example 2), 2-

[p- (methylcarbamoyloxy benzoyl cyclohexanone.

EXAMPLE 15 2- (3,4-metlzyIenea'ioxybenzoyl)cyclohexanone EXAMPLE l7 2-(p-chlorob enzoyl) cyclohexanone In the manner given in Example 2,l-piperidino-lcyclohexene was reacted with p-chlorobenzoyl chloride in Ipurification procedure 11 chloroform solution to give, after the coppercomplex purification procedure (Example 2), 2-(p-chlorobenzoyl)cyclohexanone.

EXAMPLE 18 2- (p-hydroxybenzoyl) cyclohexanone In the manner given inExample 2, l-piperidino-lcyclohexene was reacted with p-acetoxybenzoylchloride in chloroform solution to give, after the copper complex(Example 2), Z-(p-acetoxybenzoy1)cyclohexanone. The thus-obtainedZ-(p-acetoxybenzoy1)cyclohexanone was subjected to alkaline hydrolysis,the mixture acidified and the 2-(p-hydroxybenzoyl) cyclohexanonerecovered by extraction.

EXAMPLE 19 2-(0-methylbenz0yl) cyclohexanone In the manner given inExample 2, l-piperidino-lcyclohexene was reacted with o-methylbenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(o-methylbenzoyl) cyclohexanone.

EXAMPLE 20 2-(p-metlzylbenzoyl)cyclohexanone In the manner given inExample 2, l-pyrrolidino-lcyclohexene was reacted with p-methylbenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), Z-(p-methylbenzoyl) cyclohexanone ofmelting point 108ll0 C.

EXAMPLE 21 2- (2 ,4 -dz'm ethyl benzoyl cyclohexanone In the mannergiven in Example 2, l-pyrrolidino-lcyclohexene was reacted with2,4-dimethylbenzoyl chloride in chloroform solution to give, after thecopper complex purification procedure (Example 2), 2-(2,4-dimethylbenzoyl)cyclohexanone of melting point 5 1-525 C.

EXAMPLE 22 2- (3-methoxy-4-methylberzzoyl) cyclohexanone In the mannergiven in Example 2, l-piperidino-lcyclohexene was reacted with2methoxy-4-methylbenzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2), 2-(2-methoxy-4-methylbenzoyl) cyclohexanone.

EXAMPLE 23 2- (2-hydr0xy-5-chl0r0benzoyl cyclohexanone In the mannergiven in Example 2, l-piperidino-l- I cyclohexene was reacted with2-acetoxy-5-chlorobenzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2),2-(2-acetoxy-S-chlorobenzoyl) cyclohexanone. The thus-obtained2-(2-acetoxy 5 chlorobenzoyl)cyclohexanone was subjected to alkalinehydrolysis, the mixture acidified and the 2-(2-hydroxy-5chlorobenzoyl)cyclohexanone recovered by extraction.

EXAMPLE 24 2- (p-allyloxybenzoyl) cyclohexanone In the manner given inExample 2, l-piperidino-l-cyclohexene was reacted with p-allyloxybenzoylchloride in chloroform solution to give after the copper complexpurification procedure (Example 2), Z-(p-allyloxybenzoyl) cyclohexanone.

EXAMPLE 25 2- [p-(carboxymelhoxy) benzoyl] cyclohexanone;

In the manner given in Example 2, l-piperidino-lcyclohexene was reactedwith p-(carboxymethoxy)benzoyl chloride in chloroform solution to give,after the copper complex purification procedure (Example 2),2-[p-(carboxymethoxyl benzoyl] cyclohexanone.

EXAMPLE 26 2- (p-benzoyloxybenzoyl cycloheptanone In the manner given inExample 2, l-pyrrolidino-lcycloheptene was reacted withp-benzyloxybenzoyl chloride in chloroform solution to give after thecopper complex purification procedure (Example 2),2-(p-benzoyloxybenzoyl) cycloheptanone.

EXAMPLE 27 2- p-ethoxyberzzoyl cyclooctmzone In the manner given inExample 2, l-morpholino-lcycloocten was reacted with p-ethoxybenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2- (p-ethoxybenzoyl)- cyclooctanone.

EXAMPLE 28 2- (2,3 ,4-trimeth0xybenz0yl cyclooctanone In the mannergiven in Example 2, l-piperidino-lcyclooctene was reacted with2,3,4-trimethoxybenzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2), 2-(2,3,4-trimethoxybenzoyl) cyclooctanone.

EXAMPLE 29 2- (p-bromobenzoyl) cyclooczanone In the manner given inExample 2, l-piperidino-lcyclooctene was reacted with p-bromobenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(p-bromobenzoyl)- cyclooctanone.

EXAMPLE 30 Z-(S-methylbenzoyl) cyclooctanone 2- (3 ,5 -diiodobenzoyl)cyclopentanone;

2- p-fiuorobenzoyl cyclohexanone;

2- 2-methoxy-4-chlorobenzoyl) cyclohexanone;

2- 2-methoxy-3-methylbenzoyl cyclohexanone;

2- (2-methyl-4-trifiuoromethylbenzoyl cyclohexanone; 2- 3,4-dipropylbenzoyl) cycloheptanone;

v 2- 2,5 -dichlorobenzoyl cycloheptanone 2- 3 ,4-dichlorobenzoyl)cyclooctanone; 2- (p-propoxybenzoyl) cyclooctanone; 2- (2,5-diiodobenzoyl) cycloheptanone; 2- (3 -fiuorobenzoyl) cyclopentanone;

(p-bromobenzoyl) cyclopentanone; (p-hexylbenzoyl) cyclopentanone;(3-pentylbenzoyl cyclohexanone; (2-butylbenzoyl) cyclohexanone;(2-propylbenzoyl) cycloheptanone;

(3 -ethylbenzoyl cyclooctanone;

2- Z-methoxy-S -bromo) cyclopentanone; 2-benzoylcyclooctanone;2-benzoylcycloheptanone;

and the like.

13 EXAMPLE 31 3,4,54rimetlzoxyphenyl Z-piperidino-I-cyclohexenl-ylketone A mixture consisting of 35 g. (0.12 mole) of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone, 30.6 g. (0.36 mole) of piperidine, 960ml. of toluene, and 0.8 g. of p-toluenesulfonic acid was refluxed for 23hours under nitrogen using an azeotropic separator (during this time 1.8ml. of water was collected). The mixture was thereupon evaporated todryness to give partially crystalline 3,4,5-trimethoxyphenyl2-piperidino-l-cyclohexen-l-yl ketone.

EXAMPLE 32 ot-(3,4,5-trimethxyphenyl)-2-piperidinocyclohexanemethanoland its hydrochloride A solution of 3,4,5-trimethoxyphenylZ-piperidino-lcyclohexen-1-yl ketone [prepared from 35 g. of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone and 30.6 g. of piperidine, as in Example31] in 300 ml. of ethanol was hydrogenated in the presence of 1.2 g. ofplatinum oxide at an initial pressure of 50.1 pounds of hydrogen. Twomolar equivalents of hydrogen were taken up during 3.5 hours. Themixture was filtered through a filter aid and evaporated to dryness. Theoily residue was dissolved in 400 ml. of ether and 400 ml. of 10%aqueous hydrochloric acid was added. The thus-obtained reaction mixturewas stirred for 0.5 hour. A suspension was obtained which was filtered,yielding an original filtrate and a solid which was washed with ether.The solid was twice recrystallized from methanol to give 14.7 g. ofot-(3,4,5-trimethoxyphenyl)-2-piperidinocyclohexanemethanolhydrochloride of melting point 265-266" C. An analytical sample,prepared by additional recrystallization from methanol had a meltingpoint of 266267 C.

Ultraviolet: sh. 228 (8,100); sh. 232; r 269 (825); sh. 278 (612).

Analysis.-Calcd. for C H NO -HCl (percent): C, 63.06; H, 8.57; Cl, 8.87;N, 3.50. Found (percent): C, 62.99; H, 8.24; Cl, 8.66; N, 3.46.

The above original filtrate was separated into layers, the aqueous layerwas extracted with ether and then basified and extracted with methylenechloride. The extract was washed with water and saturated salt solution,then dried by pouring through anhydrous sodium sulfate and thewater-free solution was evaporated to give 5.0 g. of an oil. The oil wasconverted to the hydrochloride with ethereal hydrogen chloride to give asecond crop of 0.7 g. of (It-(3,4,5trimethoxyphenyl)-Z-piperidinocyclohexanemethanol hydrochloride (totalyield 32%; 15.4 g.).

The ether layer, after washing, drying and evaporation, gave 6.1 g. ofan oil which was redissolved in ether and allowed to crystallize,yielding 0.5 g. of a-(3,4,5-trimethoxyphenyl)-2-hydroxycyclohexanemethanol of melting point 130131 C.(after additional recrystallization from ether).

Analysis.-Calcd. for C H O (percent): C, 64.84; H, 8.16. Found(percent): C, 64.69; H, 8.29.

EXAMPLE 33 3,4,5-trimethoxyphenyl Z-morpholino-I-cyclohexene-I-yl ketoneIn the manner manner given in Example 31, 8.75 g. of2-(3,4,5-trimethoxylbenzoyl)cyclohexanone, 7.84 g. of morpholine, 240ml. of benzene and 0.2 g. of p-toluenesulfonic acid was refluxed undernitrogen for a period of 23 hours whereby 0.49 ml. of water wascollected. The solution was evaporated and the material worked up as inExample 31 to give 3,4,5-trimethoxyphenyl 2-morpholinol-cyclohexen-l-ylketone.

14 EXAMPLE 34at-(3,4,5-trimezlzoxyphenyl)-2-mol'pholilzocyclohexanemethanol and itshydrochloride A solution of 3,4,5-trimethoxyphenyl 2-morpholino-1-cyclohexen-l-yl ketone [produced as in Example 33 from 8.75 g. of2-(3,4,5-trimethoxybenzoyl)cyclohexanone] in ml. of ethanol washydrogenated in the presence of 0.3 g. of platinum oxide catalyst at aninitial hydrogen pressure of 52.5 pounds. Two molar equivalents ofhydrogen were taken up during a period of 6 hours. The mixture wasfiltered through diatomaceous earth (Filtercel) and evaporated todryness. The resulting oil was dissolved in 100 ml. of 10% aqueoushydrochloric acid, 100 ml. of ether was added and the mixture wasstirred for /2 hour. The aqueous layer was extracted twice with two50-ml. portions of ether. The ether extracts were combined, washed withwater, then with saturated salt solution, and finally dried by passagethrough anhydrous sodium sulfate. The thus-obtained solution wasevaporated to give 2.3 g. of an oily material which aftercrystallization from ether gave 1 g. of 1-(3,4,5-trimethoxybenzoyl)-l-cyclohexene of melting point 73-74 C.

The above aqueous layer was cooled in ice, basified by adding sodiumhydroxide solution and extracted with methylene chloride (three portionsof 100 ml.). The extracts were combined, washed with water and saturatedsalt solution, and dried by passing through anhydrous sodium sulfate.The thus-obtained solution Was concentrated to give 7.89 g. of an oilymaterial which was converted to the hydrochloride by adding a solutionof hydrogen chloride in ether. The solid thus obtained wasrecrystallized from methanol-ether to give 5 g. (42% yield) of oc-(3,4,5 -trimethoxyphenyl -2-morpholinocyclohexanemethanol hydrochlorideof melting point 205- 206 C.

Ultraviolet: sh. 228 (8,150); sh. 236 (6,350); A 2 69 (788); sh. 278(555).

Analysis.Calcd. for C H NO -HCl (percent): C, 59.76; H, 8.03; Cl, 8.82;N, 3.49. Found (percent): C, 59.81; H, 8.52; CI. 8.52; N, 3.57.

EXAMPLE 35 3,4,5-trimeth0xyphenyl 2-(4-mezhyl-1-piperazinyl)- 1-cyclohexen-1 -yl ketone A mixture of 8.75 g. (0.03 mole) of2*(3,4,5-trimethoxybenzoyl)cyclohexanone, 9 g. (0.09 mole) ofN-methylpiperazine, 240 ml. of toluene and 0.2 g. of p-toluenesulfonicacid was refluxed in a nitrogen atmosphere for a period of 7 hours.After 7 hours, 0.6 ml. of water had been collected in an azeotropicseparator. The reaction mixture was thereupon evaporated to dryness togive 3,4,5 trimethoxyphenyl 2 (4 methyl-1-piperazinyl)-l-cyclohexen-l-yl ketone.

EXAMPLE 3 6 06- (3 ,4,5 -zrimreth oxyphenyl -2- (4 -methy [-1 -piperazinyl cyclohexanemethanol dihydrochloride A solution of3,4,5-trimethoxyphenyl 2-(4-methyl-1- piperazinyl)-l-cyclohexen-1-ylketone, prepared from 8.75 g. of2-(3,4,5-trimethoxybenzoyl)cyclohexanone as in Example 35, was dissolvedin 100 ml. of methanol and then hydrogenated in the presence of 0.3 g.of platinum oxide at an initial pressure of 54 pounds. After 6.5 hours,the hydrogenation became sluggish, therefore, 0.03 mole of acetic acidand 0.3 g. of platinum oxide were added. After another period of 3 hoursa total of 2 molar equivalents of hydrogen was absorbed. The mixture wasfiltered through diatomaceous earth (Filtercel) and evaporated todryness. The resulting oil was dissolved in 100 ml. of 10% aqueoushydrochloric acid and 100 ml. of ether and the solution was stirred for0.5 hour. The aqueous layer was extracted with three SO-ml. portions ofmethylene chloride. The extracts were discarded. The aqueous solutionwas then basified and extracted with four portions of 50 ml. each ofmethylene chloride. The methylene chloride extracts were combined,washed with water and with saturated salt solution, dried by passingthrough anhydrous sodium sulfate and evaporated to give 5.9 g. of oil.This oil was dissolved in ether and then acidified with 35 ml. of 2 Nethereal hydrogen chloride. The resulting solid was recrystallized frommethanol, yielding 4.4 g. (31% yield) ofa-(3,4,5-trimethoxypheny1)-2-(4-methyll-piperazinyl)cyclohexanemethanoldihydrochloride hemimethanol solvate of melting point 232-233 C.

Ultraviolet: sh. 228 (8,400); sh. 234.5 (6,850); 8 270.5 (980); sh. 278(915).

Analysis.-Calcd. for C H N O -2HCl- /2CH OH (percent): C, 55.24; H,8.19; Cl, 15.17; N, 5.99. Found (percent): C, 54.90; H, 8.05; Cl, 15.30;N, 6.58.

The dihydrochloride above (1 g.) was treated with the calculated amountof aqueous sodium hydroxide solution and the mixture was extracted withmethylene chloride. The methylene chloride extract was evaporated andthe thus-obtained residue was recrystallized twice from methanol to givea-(3,4,5-trimethoxyphenyl)-2-(4-methyl-1- piperazinyl)cyclohexanemethanol.

EXAMPLE 37 p-Me'thoxyphenyl Z-piperidino-l-cyclJ1exen-1-yl ketone In themanner given in Example 31, 23.2 g. (0.1 mole) of2-(p-methoxybenzoyl)cyclohexanone was heated with 25.5 g. (0.3 mole) ofpiperidine in 800 ml. of toluene in the presence of 0.67 g. ofp-toluenesulfonic acid to give p-rnethoxyphenyl 2 piperidino 1cyclohexen-l-yl ketone.

EXAMPLE 38 Cis-A-a- (p-methoxyph'enyl) -2-piperidinocyclohexanemethanolA solution of p-methoxyphenyl 2-piperidino-1-cyclohexen-l-yl ketone(obtained from a synthesis of the same scale as shown in Example 37) in300 ml. of ethanol was hydrogenated in the presence of 1 g. of platinumoxide under an initial hydrogen pressure of 51 pounds. Two molarequivalents of hydrogen were absorbed during a period of 2.5 hours. Themixture was filtered through Filtercel diatomaceous earth. The filtratewas then evaporated to dryness and the residue dissolved in 250 ml. ofether. The ether solution upon standing produced crystals which wererecovered by filtration and washed with ether. One g. of material wasobtained having a melting point 152168 C. This material afterrecrystallization from methanol-ether was found to \be thep-toluenesulfonic acid salt ofcis-A-a-(pmethoxyphenyl)-2-piperidinocyclohexanemethanol of meltingpoint 182183 C.

Ultraviolet: k 223 (21,800); sh. 256 (705); sh. 262 (980); sh. 268(1,360); 275 (1,530); 282 (1,280). AnaIysz'n QalQd for (3 11 180 5(percent): C, 65.66;

16 H, 7.84; N, 2.95; S, 6.74. Found (percent): C, 65.27; H, 7.88; N,2.89; S, 6.86.

The ethereal filtrate above was stirred with 200 ml. of 10% aqueousacetic acid for /2 hour. The aqueous layer was separated, then extractedonce With ether, and the ether extract discarded. The aqueous layer wasthen cooled, basified with aqueous sodium hydroxide solution andextracted with methylene chloride (four portions of ml. each). Theextracts were combined, washed with water, saturated salt solution,dried by passing the solution through anhydrous sodium sulfate andevaporated to give 22.5 g. of oily material. This material wasrecrystallized from petroleum ether to give 21.4 g. (71% yield) of cis-A-a-(p-methoxyphenyl) 2 piperidinocyclohexanemethanol of melting point7880 C.

Ultraviolet: A 225 (11,500); 275 (1,500); 283 (1,300).

Analysis.-Calcd. for C H NO (percent): C, 75.20; H, 9.63; N, 4.62. Found(percent): 'C, 75.17; H, 9.88; N, 4.47.

Treating cis-A-u-(p-methoxyphenyl)-2-piperidinocyclo hexanemethanol withethereal hydrogen chloride gave cis-A-u-(p-methoxyphenyl) 2piperidinocyclohexanemethanol hydrochloride of melting point 235236 C.

In subsequent examples, compounds in different isomeric forms willappear, e.g., p-methoxyphenyl 2-piperidinocyclohexyl ketone can be incis or trans isomeric forms:

cis trans The above configurations are simplified. For example, a truerrepresentation of the cis form above would be the configurations (X) and(Y) below.

l I l l i l l I l l l l l l l l In the configuration (X) thep-methoxybenzoyl group (at 1) is attached by an axial bond (a) to thecyclohexane moiety (chair form) and the piperidino group (at 2) by anequatorial bond (e). While this would indicate the existence of a cisisomer with reversed grouping, i.e., p-methoxybenzoyl on an equatorialbond and piperidino on an axial bond, such an isomer isthermodynamically less stable under ordinary conditions. However, theoptical isomers (Y) and (X) of the cis form are stable and thus thesimplified cis configuration represents a mixture of (X) and (Y). In thetrans form, the equatorial-equatorial positions of the vicinalsubstituents is the thermodynamically stable configuration and thus onlyone trans-p-methoxyphenyl Z-piperidinocyclohexyl ketone consisting oftwo optical forms, as for the cis compound, is obtained.

1 7 EXAMPLE 39 Cis-p-methoxyphenyl Z-piperidinocyclohexyl ketone Amixture of 139 g. (0.6 mole) of 2-(p-methoxybenzoyl) cyclohexanone, 153g. (1.8 moles) of piperidine, 4800 ml. of toluene and 4.02 g. ofp-toluenesulfonic acid monohydrate was refluxed for hours in a vesselequipped with an azeotropic separator. A total of 10.1 ml. of water wascollected. The reaction mixture was evaporated to dryness on a steambath to give a residue which was dissolved in 1200 ml. of ethanol andthe thus-obtained solution was divided into four equal parts. Each partwas hydrogenated in the presence of 1.5 g. of platinum oxide at aninitial pressure of 50 pounds of hydrogen. Hydrogenation was stoppedafter the uptake of 1 molar equivalent. The time required for thisprocedure was minutes to 55 minutes. Thereafter, the combined mixturewas filtered through diatomaceous earth, and the solution was evaporatedto dryness. A deep yellow oil was obtained which was dissolved in 1200ml. of ether and allowed to stand for 15 minutes. The mixture wasthereupon filtered and a precipitate was collected Weighing 5.3 g. Theethereal filtrate was stirred with 1 l. of 10% aqueous hydrochloric acidfor 45 minutes. The acidic layer was separated, filtered and basifiedwith 20% aqueous sodium hydroxide solution. The resulting oil whichsolidified after a short time was extracted with methylene chloride(five portions of 200 ml. each), the extracts were combined, washed withwater, then with saturated saltsolution, dried over anhydrous sodiumsulfate and evaporated to give a crude product of 116 g.Recrystallization of this crude product from petroleum ether gave 75 g.(42% yield) of colorless needles of cis-p-methoxyphenylZ-piperidinocyclohexyl ketone having a melting point of 8688 C. Furtherrecrystallization from petroleum ether for analytical purposes gavecis-p-methoxyphenyl 2piperidinocyclohexyl ketone of melting point86.5-88 C.

Ultraviolet: A 217 (11,850); 273 (15,800); 278 (15,500).

Analysis.Calcd. for C H NO (percent): C, 75.71; H, 9.03; N, 4.65. Found(percent): C, 76.19; H, 9.19; N, 4.88.

EXAMIPDE 40 T rans-p-methoxyphenyl Z-piperidinocyclohexyl ketone Asolution of 68.3 g. (0.227 mole) of cis-p-methoxyphenylZ-piperidinocyclohexyl ketone was refluxed for 68 hours in 683 ml. ofpiperidine. The reaction mixture was thereupon evaporated to dryness togive 55 g. of a residual oil which was dissolved in 500 ml. of ether andextracted with four portions of 100 ml. each of 10% aqueous acetic acid.The acid extracts were combined, cooled in ice and 'basified with 20%aqueous sodium hydroxide solution and thereupon extracted with fourportions of 150 ml. each of methylene chloride. The methylene chlorideextracts were combined, washed with saturated salt solution, dried overanhydrous sodium sulfate and evaporated to give 22 g. of a colorlesssolid which was crystallized from 150 ml. of petroleum ether (boilingrange from 60 C.) to give 12.05 g. of trans-p-methoxyphenylZ-piperidinocyclohexyl ketone of melting point 100101 C. A second cropof 3.5 g. of the same material was also obtained; a total of 23% yield.

Ultraviolet: A 216 (12,900); 271 (15,350).

Analysis.-Calcd. for C H NO (percent): C, 75.71; H, 9.03; N, 4.65. Found(percent): C, 75.28; H, 8.66; N, 4.62.

The original ether layer above contained also 1-(p-methoxybenzoyl)-1-cyclohexene, a yellow oil boiling at 145- 155 C.

Analysis.Calcd. for C H O (percent): C, 77.75; H, 7.46. Found (percent):C, 77.99; H, 7.57.

Treatment of 3.45 g. of 1-(p-methoxybenzoyl)-1-cyclohexene with 20 ml.of piperidine on the steam bath for a period of 8 hours produced 36 mg.of trans-p-methoxy- 18 phenyl 2-piperidi110cycl0hexy1ketone of meltingpoint 99 101 C.

EXAMPLE 41 C is-A -0cp-metlzoxyphenyl -2-piperidilzocyclohexanemethanolA solution of cis-p-methoxyphenyl 2-piperidinocyclo hexyl ketone (3.01g.; 0.01 mole) in ml. of ethanol was subjected to hydrogenation in thepresence of platinum oxide (0.3 g.) at an initial pressure of 53 poundsof hydrogen. One molar equivalent was absorbed in 25 hours. The mixturewas filtered, and the filtrate was evaporated to dryness, giving 3.1 g.of an oily material. A 2.9 g. portion of this oil was chromatographedover g. of Florisil (anhydrous magnesium silicate) using 150-ml.portions of an eluant of 6% acetone94% Skellysoive B hexanes. The firstfour fractions containing 0.126 g. were discarded. The next eightfractions (150 ml. each) using an eluant of 12% acetone-88% SkellysolveB hexanes gave 2.294 g. of solid melting at 81-82 C. Fractions 1316 (150ml. each) using an eluant of 25% acetone75% Skellysolve B hexanes gave0.309 g. of solid material melting at til-82 C. The solids were combinedand recrystallized from petroleum ether (boiling range 30-60 C.) to givein two crops 2.4 g. of cisA-e-(pmethoxyphenyl) 2piperidinocyclohexanemethanol of melting point 8182.5 C.

Since the carbon atom of the methanol group of (it"(P methoxyphenyl) 2piperidinocyclohexanemethanol is asymmetric, it is obvious that besidesthe cis-A-alcohol, the cis-B-alcohol is possible (Example 42).

EXAMPLE 42 Cis-A- and cis-B-u-(p-methoxyphenyl) -2-piperidin0-cyclohexanemeth anol Solid cisp-methoxyphenyl Z-piperidinocyclohexylketone (3.01 g.; 0.01 mole) was added to an ice-cooled solution ofsodium borohydride (3 g.) in 100 ml. of ethanol. The reaction mixturewas then stirred at room temperature (2225 C.) for a period of 16 hours.It was evaporated to dryness in vacuo at 40 C. To the residue was added100 ml. of water, and the mixture was then stirred for 30 minutes. Theresulting oil was extracted three times with ether. The ether extractswere combined, washed with water, the water discarded, then washed withfour 25-m1. portions of 10% aqueous acetic acid. The acidic extract waswashed once with ether, and the ether discarded. It was then cooled inice and basified with 15% sodium hydroxide solution. The reactionmixture was then extracted three times with ether, the extractscombined, washed with water, then with saturated salt solution, driedover anhydrous sodium sulfate and evaporated to give 3 g. of an oil. Theoily material was crystallized from 50 ml. of petroleum ether (boilingrange 3060 C.) to give 1.8 g. of cis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol, melting point 78- 80 C.

The filtrate was evaporated to dryness, and the residue waschromatographed on 60 g. of Florisil (anhydrous magnesium silicate). Thecolumn of Florisil was eluted twice with 150-ml. portions of an eluantconsisting of 6% acetone and 94% Skellysolve B hexanes; four times with150-ml. portions of an eluant consisting of 12% acetone and 88%Skellysolve B hexanes and finally three times with 150-ml. portions of a20% acetone80% Skellysolve B hexanes solution, giving 0.576 g. ofcis-A-alcohol, which after recrystallization from petroleum ether had amelting point of 8081 C. Elution with 50% acetone50% Skellysolve Bhexanes (four portions of 150 ml. each) and acetone (two portions of 250ml. each) gave 0.316 g. of cis B c (p methoxyphenyl) 2piperidinocyclohexanemethanol, which after recrystallization from etherweighed 0.1 g. and had a melting point of 135-136 C.

These cis alcohols A and B can also be produced from cis-p-methoxyphenylZ-piperidinocyclohexyl ketone by reduction with lithium aluminumhydride.

EXAMPLE 43 Cis-A- and cis-B-u-(p-methoxyphenyl)-2-piperidin0-cyclohexanemethanol A solution of 0.9 g. (3 mmoles) ofcis-p-methoxyphenyl 2-piperidinocyclohexyl ketone in 25 ml. of ether wasadded dropwise during 5 minutes to a solution containing 1 g. of lithiumaluminum hydride in 100 ml. of ether. The mixture was stirred during aperiod of 22 hours and was then decomposed by successive addition of 1ml. of water, 1 ml. of 15% aqueous sodium hydroxide and 3 ml. of water.The resulting suspension was stirred for a period of 2 hours. It wasthen filtered and the solid washed with ether. The combined filtrate andwashings were extracted with three portions of 30 ml. each of aqueousacetic acid, and the combined acidic extracts were back-washed once withether. The acidic extract was then basified with aqueous sodiumhydroxide and extracted three times with ether. The combined etherextracts were washed with water, saturated salt solution, and dried bypassage through anhydrous sodium sulfate. The resulting dried solutionwas evaporated to give 0.77 g. of a colorless oil. This oil waschromatographed over 35 g. of Florisil (anhydrous magnesium silicate) byeluting with an eluant consisting of 6% acetone and 94% Skellysolve Bhexanes. The first four fractions of 150 ml. each gave 0.607 g. (67%yield) of cis A a (p methoxyphenyl) 2- piperidinocyclohexanemethanol(melting point SO-81 C.). Further elution with an eluant consisting of12% acetone and 88% Skellysolve B hexanes gave, in four 150-ml.fractions, 0.209 g. of cis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol of melting point 134- 135C. (23% yield).

EXAMPLE 44 Trans-D-a- (p-methoxyphenyl=2-piperz'din0cycl0hexaltemethanol In the manner given in Example 41,trans-p-methoxyphenyl 2-piperidinocyclohexyl ketone (3.01 g.; 0.01 mole)was hydrogenated in ethanol solution in the presence of 0.5 g. ofplatinum oxide catalyst at 53 pounds initial hydrogen pressure. Thesolution after 138 minutes of hydrogenation was filtered throughFiltercel diatomaceous earth. The filtrate was evaporated giving 3 g. ofa solid of melting point 141145 C. This solid was crystallized frommethanol to give 2.5 g. of colorless needles of trans- C-ow(.p-methoxyphenyl -2-piperidinocyclohexanemethanol of melting point148-149 C. A second crop of 0.25 g. of product was obtained from thefiltrate; the total yield was 91%.

Ultraviolet; 225 (12,150); 275 (1,500); 281 (1,300).

Analysis.-Calcd. for C H NO (percent): C, 75.20; H, 9.63; N, 4.26. Found(percent): C, 75.18; H, 9.81; N, 4.82.

EXAMPLE 45 Tra ns-D-a- (p-methoxyphenyl -2-piperidin0cycl0hexanemethanol A solution of 0.60 g. (1.98 mmoles) oftrans-C-a-(pmethoxyphenyl)-2-piperidinocyclohexanemethanol in 4 ml. oftrifluoroacetic acid was stirred for 20 minutes. It was cooled in ice,10 ml. of water was added, followed by 10 ml. of 20% aqueous sodiumhydroxide solution. The mixture was thereupon extracted twice withmethylene chloride. The combined extract was washed with water,

saturated salt solution, dried by passage through anhydrous sodiumsulfate and evaporated to give 0.6 g. of a colorless solid of meltingpoint 129140 C. Crystallization from methanol yielded 0.325 g. ofrecovered starting material of melting point 145147 C. The filtrate wasevaporated to dryness and the residue was chromatographed over 15 g. ofFlorisil (anhydrous magnesium silicate). The column containing theFlorisil was eluted with 400 ml. of a solution containing 6% acetone and94% Skellysolve B hexanes. The filtrates from the solution were combinedand evaporated, and the residue was recrystallized from petroleum ether(boiling range 3060 C.) to give 77 mg. of a product melting at 8182 C.,namely trans-D-u- (p-methoxyphenyl 2 piperidinocyclohexanemethanol.

Ultraviolet: 226 (11,000); 276 (1,650); 282 (1,450).

Analysis.Calcd. for C H NO (percent): C, 75.20; H, 9.63; N, 4.62. Found(percent): C, 75.19; H, 9.63; N, 4.55.

EXAMPLE 46 T rans-C- and trans-D-a- (p-methoxyphenyl -2-piperidinocyclohexanemethanol A solution of trans-p-methoxyphenylZ-piperidinocyclohexyl ketone (23.9 g.; 0.0795 mole) in 575 ml. of etherwas added to a solution of 24 g. of lithium aluminum hydride in 2400 ml.of ether over a period of 30 minutes. The mixture was then stirred forabout 20 hours. It was thereupon decomposed successively with 24 m1. ofwater, 24 ml. of 15% aqueous sodium hydroxide and 72 ml. of water. Theresulting mixture was filtered and the cake was washed with ether. Thecombined filtrate and washings were evaporated to dryness to give 22.5g. of a colorless oily solid which upon crystallization from 75 ml. ofethano]v gave 13.4 g. oftrans-C-ot-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol of meltingpoint 145146 C.

The filtrate was evaporated to dryness. The residue was dissolved in 50ml. of methylene chloride and chromatographed over 460 g. of Florisil(anhydrous magnesium silicate). The column containing the Florisil waseluted with 750 ml. of an eluant consisting of 3% acetone and 97%Skellysolve B hexanes. This fraction yielded 81 mg. of solid which Wasdiscarded; thereupon were taken nineteen 250-ml. portions using aneluant consisting of 6% acetone and 94% Skellysolve B hexanes. Thesefractions were combined and evaporated to give 5.31 g. of solid meltingat -82 C. Further elution with an eluant consisting of 15% acetone andSkellysolve B hexanes (4 fractions of 250 ml. each) gave 0.535 g. ofsolid melting at 80-81 C. Recrystallization of the combined materialfrom petroleum ether afforded 4.6 g. of trans-D-a- (p-methoxyphenyl) 2piperidinocyclohexanemethanol of melting point 81 82 C.

Nuclear magnetic resonance spectrum (in CD013) showed methoxy at 229cps; broad band for benzylic hydrogen centered at 278.5 cps.

EXAMPLE 47 Cis-B-a- (p-methoxyphenyl)-2-piperidinocyclohexane methanol Asolution was prepared having 30.3 g. (0.1 mole) ofcis-A-a-(p-methoxyphenyl) 2 piperidinocyclohexanemethanol in 200 ml. oftrifiuoroacetic acid, under cooling with ice. The mixture was thenstirred at room temperature for 20 minutes, giving greenish solutionwhich was again cooled in ice. To this solution was added g. of icefollowed by 500 ml. of water and then 500 ml. of 20% aqueous sodiumhydroxide. The mixture was stirred for 15 minutes and was thereuponextracted with five portions of 200 ml. each of methylene chloride. Themethylene chloride extracts were combined, washed with water, saturatedsalt solution, then dried by passage through anhydrous sodium sulfateand evaporated to dryness to give 28 g. of a colorless oil. This oil wasdissolved in 1 l. of ether and the solution was concentrated to about200 ml. at which point crystallization commenced. The solution wasallowed to cool and was then filtered to provide 16.4 g. ofcis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol as needlesmelting at 133134 C. From second and third crops, additional 6.8 g. ofcis- B-u-(p-methoxyphenyl) 2 piperidinocyclohexanemethanol was obtained.

Analysis.-Calcd. for C H NO (percent): C, 75.20; H, 9.63; N, 4.62. Found(percent): C, 74.96; H, 9.62; N, 4.55.

EXAMPLE 48 t-(3, 4, S-trimethoxyphenyl)-2-(hexahydl o-lH-azepin-I-yl)cyclohexanemellzanol hydrochloride 0 oorn g l -oon n01 H 511 3 NJH00H:

A mixture of 35 g. (0.12 mole) of2-(3,4,5-trimethoxybenzoy1)cyclohexanone, 35.6 g. (0.36 mole) ofhexamethyleneimine, 960 ml. of toluene and 0.8 g. of p-toluenesulfonicacid was refluxed for 7.5 hours in a nitrogen atmosphere in a vesselequipped with an azeotropic separator. A total of 1.8 ml. of water wascollected. The mixture was thereupon evaporated to dryness, the residuewas dissolved in 250 ml. of ethanol and hydrogenated in the presence of1.2 g. of platinum oxide at an initial pressure of 51.5 pounds ofhydrogen. Two molar equivalents of hydrogen were absorbed during 5hours. The reaction mixture was then filtered through diatomaceous earth(Filtercel), and the filtrate was evaporated to dryness. Thethus-obtained residue was dissolved in 400 ml. of ether. The ethersolution was stirred with 400 ml. of hydrochloric acid for 0.5 hour, andthe resulting suspension was filtered. The obtained solid was washedwith ether to give 18.2 g. of material. This material was crystallizedfrom 250 ml. of methanol to give 16.4 g. of a-(3,4,5 trimethoxyphenyl) 2(hexahydro-lH-azepin-l-yl)cyclohexanemethanol hydrochloride of meltingpoint 244- 246 C.

Ultraviolet: sh. 228 (8,250); 268 (757); 276 (608).

Arzalysis.Calcd. for C H NO -HCl (percent): C, 63.83; H, 8.77; Cl, 8.56;N, 3.38. Found (percent): C, 63.95; H, 9.13; CI, 8.47; N, 3.58.

Workup of the aqueous hydrochloric acid filtrate above provided another0.7 g. of a-(3,4,5-trimethoxyphenyl)-2- (hexahydrolH-azepinl-yl)cyclohexanerneth anol hydrochloride of melting point 242243 C.; thus atotal yield of 34%.

EXAMPLE 49 Cis-A-ap-methoxyphenyl -2-( hexahydro-I H -azepin-1-yl)cyclohexanemethanol hydrochloride (A)1-HEXAMETHYLENEIMINO-l-CYCLOHEXENE A mixture of 196 g. (2 moles) ofcyclohexanone, 396 g. (4 moles) of hexamethyleneimine, 3 l. of benzeneand 2.5 g. of p-toluenesulfonic acid was refluxed for 24 hours,separating 34 ml. of water with an azeotropic separator. Distillation ofthe material provided 293.7 g. (82% yield ofl-hexamethyleneimino-l-cyclohexene having a boiling point of 138-140 C.at 16 mm. [this enamine was reported by Nightingale et al., J. Org.Chem. 28, 642 1963 AZEPIN 1 YL)-CYCLOHEXANEMETHANOL HYDRO- CHLORIDE To asolution of 107.4 g. (0.6 mole) of 1-hexamethyleneimino-l-cyclohexene in252 ml. of chloroform (purified by passage through basic alumina) wasadded 60.6 g.

0.6 mole) of triethylamine at a temperature of 5 C. To the reactionmixture was added a solution of 102 g. (0.6 mole) of p-anisoyl chloridein 240 ml. of purified chloroform during a period of 2 hours whilekeeping the temperature between 5 to 10 C. A suspension resulted whichwas stirred for a period of about 20 hours at room temperature. Thesuspension was thereupon filtered, and the precipitate washed withether, the ether wash being discarded. The precipitate was 46.8 g. oftriethylamine hydrochloride of melting point 253254 C. The chloroformfiltrate was evaporated to dryness. The resulting residue was dissolvedin 900 ml. of ethanol and hydrogenated in three portions, each in thepresence of l g. of platinum oxide at a hydrogen pressure of about 50-52pounds. After the absorption of about of the hydrogen had taken place,the hydrogenation stopped and another 1 g. of platinum oxide was added.Two molar equivalents of hydrogen were absorbed during 22 hours. Theresulting thick suspension was filtered and the precipitate washed withethanol. The moist cake was refluxed with 1500 ml. of ethanol, filteredand allowed to crystallize. The first crop of crystals amounted to 80.7g. of cis-Aa-(p-methoxyphenyl)-2-(hexahydro 1Hazepin-l-yl)cyclohexanemethanol hydrochloride of melting point of 230-231 C. A second crop of 20 g. was also collected. Furtherrecrystallization did not change the melting point of the product.

Ultraviolet: A 226 (12,150); 276 (1,550); 282 (1,350).

AnaIysis.-Calcd. for C l-l NO -HCl (percent): C, 67.87; H, 9.12; Cl,10.02; N, 3.97.. Found (percent): C, 67.27; H, 9.14; Cl, 9.97; N, 4.03.

EXAMPLE 5 0 0tp- Trifluoromethyl phenyl -2- (hexahydro-I H -aze pin- 1-yl cy cl o hexanem ethanol hydrochloride In the manner given in Example49, 0.1 mole of triethylamine and 0.1 mole ofl-hexamethyleneimino-lcyclohexene was reacted in chloroform solutionwith 0.1 mole of p-trifiuoromethylbenzoyl chloride. The resultingproduct was hydrogenated in 300 ml. of methanol in the presence of 1 g.of platinum oxide. Two molar equivalents of hydrogen were absorbed in3.5 hours. The hydrogenation reaction mixture was filtered throughdiatomaceous earth (Filtercel) and the filtrate evaporated to dryness.The resulting solid was suspended in 200 ml. of ether and 200 ml. of 10%aqueous acetic acid, and the suspension was stirred for a period of 3.5hours. The suspension was then filtered, and the solid washed with waterfollowed by ether. Thirteen and four-tenths g. of solid was thusobtained which was recrystallized from methanol givingnt-(p-trifiuoromethylphenyl) 2(hexahydro-lH-azepinl-yl)cyclohexanemethanol hydrochloride of meltingpoint 263264 C.

Ultraviolet: a 216 (8,050); 252 (298); 257 (357); 263 (364);269 (290).

Analysis.-Calcd. for C H F NO-HCl (percent): C, 61.29; H, 7.46; Cl,9.05; F, 14.54; N, 3.57. Found (percent): C, 60.89; H, 7.58; Cl, 9.17;F, 13.96; N, 3.66.

EXAMPLE 5 1 OL-( p-Chloro phe'nyl -2-(hexahydro1 H -azepin-1 -ylcyclohexanemethanol hydrochloride 1n the manner given in Example 49*,0.1 mole of triethylamine, 0.1 mole ofl-hexamethyleneimino-l-cyclohexene and 0.1 mole of p-chlorobenzoylchloride were reacted in purified chloroform and the resulting producthydrogenated for 5.5 hours in 30 0 ml. of methanol in the presence of 1g. of platinum oxide. The resulting suspension was diluted with 400 ml.of ethanol, heated to reflux, filtered and the solution allowed tocrystallize. Filtration yielded 12.25 g. ofa-(p-chlorophenyl)-2-(hexahydro-1H- azepin-l-yl)cyclohexanemethanolhydrochloride of melting point 274275 C.

23 Ultraviolet: A 221 (10,000); sh. 226 (8,200); 252 (182);258 (210);267(260 275 (193).

Analysis.Calcd. for C H ClNO-HCl (percent): N, 3.91. Found (percent): N,3.98.

EXAMPLE 52 a-PhenyI-Z-(hexahydro-IH-azepin-l-yl)cyclohexanemethanolhydrochloride In the manner given in Example 49, 0.1 mole oftriethylamine, 0.1 mole of l-hexamethyleneimino-l-cyclohexane and 0.1mole (14 g.) of benzoyl chloride were reacted, and the reaction producthydrogenated in methanol in the presence of platinum oxide for a periodof 2.5 hours. The mixture was filtered, evaporated to dryness and thesolid residue was suspended in 200 ml. of ether and 200 ml. of 10%aqueous acetic acid. The mixture was stirred for 0.5 hour and theresulting suspension filtered yielding a solid which was washed withwater followed by ether. The thus-obtained product, 3.6 g., wasrecrystallized from methanol to give 2.8 g. ofa-phenyl-2-(hexahydro-lH-azepin 1 yl)cyclohexanemethanol hydrochlorideof melting point 276-277 C.

Ultraviolet: A 247 (107); 252 (130); 257 (178); 263 (130);267 (91).

An.aylsis.-Calcd. for C H NO-HCl (percent): C, 70.45; H, 9.34; Cl,10.95; N, 4.33. Found (percent): C, 70.22; H, 8.94; CI, 11.03; N, 4.45.

EXAMPLE 53 ot- (3,4-methylenedixy phenyl -2- hexahydro-I H -azepin-1-yl) cyclohexanemethanol hydrochloride A solution of piperonyloylchloride in 120 ml. of chloroform Was added during 1.5 hours withcooling and stirring to a solution of l-hexamethyleneimino-l-cyclohexane(53.6 g.; 0.3 mole) and 30.3 g. (0.3 mole) of triethylamine in 126 ml.of chloroform at a temperature below 10 C. The reaction mixture was thenstirred for about 20 hours at a temperature between 2326 C. Thethusobtained suspension was filtered to give 23 g. of triethylaminehydrochloride melting at 252-254 C. The filtrate was evaporated todryness, the residue was dissolved in 600 ml. of ethanol andhydrogenated in the presence of 3 g. of platinum oxide at an initialpressure of 52.5 pounds of hydrogen. After 6 hours, a 1 g. quantity ofplatinum oxide catalyst was added and hydrogenation continued foranother 16 hours. The resulting suspension was filtered and the solid,consisting of the product and catalyst, was refluxed in 1800 ml. ofethanol; this suspension was filtered, evaporated to 900 ml. and allowedby crystallize, yielding 50 g. of a-(3,4-methylenedioxyphenyl)-2-(hexahydro 1H-azepin-1-yl) cyclohexanemethanol hydrochloride of meltingpoint 235-236 C.

Work-up of the filtrate by evaporation and stirring with 400 ml. of 10%aqueous acetic acid and 450 ml. of ether gave another 10 g. of solidmaterial which after recrystallization from ethanol gave g. ofa-(3,4-methylenedioxyphenyl)-2-(hexahydro-lH-azepin 1yl)cyclohexanemethanol hydrochloride of melting point 233234 C.

Ultraviolet: Amax 235 (4,150); 286 (4,050).

Anaylsis.-Calcd. for C H NO -HCl (percent): C, 65.29; H, 8.22; CI, 9.64;N, 3.81. Found (percent): C, 65.18; H, 8.38; Cl, 9.93; N, 3.79.

The above compound is useful as a diuretic and oral antidiabetic agent.

EXAMPLE 54 a- (3,4-dimethoxyphenyl)-2-(hexahydro-lH-azepin-I -yl)cyclohexanemethanol hydrochloride In the manner given in Example 53,1-hexanemethyleneimino-l-cyclohexane was reacted with3,4-dimethoxybenzoyl chloride (53.6 g.; 0.3 mole) in the presence oftriethylamine. The resulting product was hydrogenated in the presence ofplatinum oxide and the mixture was worked up as in Example 53 giving52.2 g. of (l-(3,4-

24 dimethoxyphenyl)-2-(hexahydro-1H-azepin 1 yl)cyclohexanemethanolhydrochloride of melting point 225-228 C. in the first crop. Additionalmaterial was obtained by the work-up of filtrates with actice acid andether. A total yield of about 50% was obtained. The analytical sample,prepared by recrystallization from ethanol, gaveot-(3,4-dimethoxyphenyl) 2 (hexahydro 1H azepin-1-yl)cyclohexanemethanol hydrochloride of melting point 225-226 C.

Ultraviolet: Amax, 230 (8,550); 279 (2,950); sh. 285 (2,550).

Analysis.-Calcd. for C H NO -HCl (percent): C, 65.69; H, 8.93; CI, 9.24;N, 3.65. Found (percent): C, 65.88; H, 9.19; Cl, 9.30; N, 3.95.

EXAMPLE 55 Cis-B-a-(p-methoxyphenyl)-2-(hexahydro IH-azepin-I-yl)cyclohexanemethanol and the hydrochloride thereof To 240 ml. oftrifiuoroacetic acid, cooled to 5 C. was added, all at once, 38 g. (0.12mole) of cis-A-a-(p-methoxypheny) 2 (hexahydro 1H asepin 1yl)cyclohexane methanol with stirring. The mixture was kept stirring for20 minutes whereby the temperature reached about 40 C. Thereupon, thesolution was cooled, ice was added, followed by 600 ml. of water andthen 600 ml. of 20% aqueous sodium hydroxide. The mixture was thenextracted with five 200-ml. portions of methylene chloride. The extractswere combined, washed with saturated salt solution, dried by passingthrough anhydrous sodium sulfate, and the filtrate evaporated to give37.9 g. of a yellowish oil. This oil was dissolved in ml. of petroleumether (boiling range 3060 C.) and allowed to crystalize in therefrigerator overnight; 13.6 g. of crystals were recovered byfiltration. These crystals were recrystallized from 50 ml. of ether togive 10.1 g. of cis-B-a-(p-methoxyphenyl) 2 (hexahydro 1H azepin 1yl)cyclohexanemethanol of melting point 94-95 .5 C.

Ultraviolet: Amax. 225 (12,750); 275 (1,550); 281 (1,350).

Analysis.-Calcd. for C H NO (percent): C, 75.67; H, 9.84; N, 4.41. Found(percent): C, 75.86; H, 9.85; N, 4.48.

The hydrochloride of cis-B-u-(p-methoxyphenyl) 2- (hexahydro-lH-azepin 1yl)cyclohexanemethanol was prepared with 1.5 N ethereal hydrogenchloride. After two crystallizations from methanol-ether, colorlessneedles were obtained melting at 188189 C.

Ultraviolet: 226 (12,700); 275 (1,450); 281 (1,250).

Analysis.Calcd. for C H NO -HCl (percent): C, 67.87; H, 9.12; Cl, 10.02;N, 3.97. Found (percent): C, 67,24;H, 9.36; CI, 9.76; N, 3.96.

Oxidation of both cis-A- and cis-B-a-(p-methoxyphenyl) 2 (hexahydro 1Hazepin 1 yl)cyclohexanemethanol with chromic acid (Jones reagent) gavethe same cis-p-methoxyphenyl 2-(hexahydro-1H-azepin-l-yl) cyclohexylketone as a pale yellow oil. Treating this oil with hydrogen chloride inether provided after recrystallizing from methanol-ether thehydrochloride of cis-pmethoxyphenyl 2 (hexahydro 1H azepin 1 yl)cyclohexyl ketone of melting point 164165 C.

Analysis.-Calcd. for C H NO -HCl (percent): C, 68.26; H, 8.59; Cl,10.08; N, 3.98. Found (percent): C, 67.92; H, 8:55; Cl, 10.06; N, 4.05.

EXAMPLE 56 ot-(3,4,S-trimethoxyphenyl)-2-piperidinocycloheptane methanolhydrochloride (A) 1-PIPERIDINO-1-CYCLOHEPTENE A mixture of 224.8 g. (2moles) of cycloheptanone, 340 g. (4 moles) of piperidine, 400 ml. ofbenzene and 2.2 g. of p-toluenesulfonic acid was refluxed for a periodof 16 hours in a nitrogen atmosphere, using an azeotropic separator. Atotal of 5 ml. of water was collected. Since this was less than thecalculated amount of water produced during the reaction, the separatorwas replaced with a Soxhlet extractor containing 322 g. of crystallineSodium aluminum silicate, N312 [(Al O2)12(SiO2)12] [Linde molecularseive, Type 4a; see The Merck Index, Merck and Co., Inc. 1960, Seventhedition, page 1592], and the mixture was refluxed for three days. Afterthe solvent was removed by distillation from the reaction mixture, 319.7g. of l-piperidino-l-cycloheptene of boiling point l30-l3l C. at 17 mm.(89% yield) was obtained.

(13m(3,4,B-TRIMETHOXYPHENYL)-2-PIPER1DINOCY- CLOHEITANEMETHANOLHYDROCHLORIDE In the manner given in Example 49, Part B, 23 g. (0.1mole) or 3,4,5-trimethoxybenzoyl chloride, 17.9 g. (0.1 mole) of1-piperidino-l-cycloheptene and triethylamine (0.1 mole) were reacted atlow temperature in a chloroform solution. The resulting product washydrogenated in methanol for a period of 3 hours during which 2 molarequivalents of hydrogen were consumed. The resulting reaction mixturewas then filtered and evaporated and the residue stirred with 150 ml. ofwater and 150 ml. of methylene chloride for a perior of 0.5 hour. Themethylene chloride layer was separated and stirred with 250 ml. of 10%aqueous hydrochloric acid for /2 hour. The resulting suspension wasfiltered and the solid washed with water to give 7.5 g. ofu-(3,4,5-trimethoxyphenyl)-2- piperidinocycl-oheptanemethanolhydrochloride of melting point 237238 C. This material wasrecrystallized from methanol to giveoz-(3,4,S-trimethoxyphenyltZ-piperidino'cycloheptanemethanolhydrochloride of melting point 243-244 C.

Ultraviolet: sh. 266 (8,250); sh. 234 (6,800); k 270 (782); sh. 278(546).

Analysis.--Calcd. for C H NO -HCl (percent): C, 63.82; H, 8.77; Cl,8.57; N, 3.38. Found (percent): C, 63.43; H, 8.85; Cl, 8.66; N, 3.20.

The work-up of the methylene chloride layer gave 1.5 g. of cycloheptyl3,4,5-trimethoxyphenyl ketone of melting point 7677 C. in colorlesscrystalline plates.

Analysis.--Calcd. for C I-T (percent): C, 69.83; H, 8.27. Found(percent): C, 69.64; H, 8.24.

EXAMPLE 57 u- (3,4,5 -trimelh0xyphenyl -2-( 1 -pyrrolidz'nylcyclohexanemethanol and hydrochloride A mixture of 17.5 g. (0.06 \mole)of 2-(3,4,5-trimethoxybenzoyDcyclohexanone, 12.8 g. (0.18 mole) ofpyrrolidine and 480 ml. of benzene was refluxed for 1.25 hours using anazeotropic separator; 1.5 ml. of water was collected. The mixture wasevaporated to dryness to give a yellow oil. A small sample wascrystallized twice from ether to give yellow prisms melting at 118-l20C. and constituting 3,4,5-trimethoxyphenyl2-(l-pyrroldinyl)-lcyclohexen-l-yl ketone.

Ultraviolet: in ether k 262 (11,500); 358 (5,550); in ethanol sh. 220(17,000); 269 (7,700); 372 (7,050).

AnaIysis.-Calcd. for C H NO (percent): C, 69.54; H, 7.88; N, 4.06. Found(percent): C, 69.91; H, 8.08; N, 3.76.

The crude 3,4,5trimethoxyphenyl 2-(1-pyrrodinyl)-1- -cyclohexen-l-ylketone was dissolved in 250 ml. of ethanol and hydrogenated in thepresence of 0.6 g. of platinum oxide. Two molar equivalents of hydrogenwere taken up in 6 hours. The mixture was then filtered throughdiatomaceous earth and the filtrate evaporated to dryness. The residuewas stirred with 200 ml. of 10% aqueous hydrochloric acid and 250 ml. ofether for 0.5 hour. The aqueous layer was separated, extracted withether, basified with sodium bicarbonate and extracted with four 125-ml.portions of methylene chloride. The methylene chloride extracts werecombined, washed with water, then with saturated salt solution, dried bypassing through anhydrous sodium sulfate and evaporated to give 16.5

26 g. of solid. This solid was recrystallized from ether to give 9.7 g.of zit-(3,4,5-trimethoxyphenyl)-2-(l-pyrrolidinyl)cyclohexanemethanol ofmelting point 121-122" C. A second crop of 2 g. of the alcohol wasobtained with a melting point of 119-120 C. The total yield was 56%.

Ultraviolet: sh. 226 (9,200); A 269 (744); sh. 280 (542).

Analysis.-Calcd. for C H NO (percent): C, 68.74; H, 8.94; N, 4.01. Found(percent): C, 68.61; H, 8.84; N, 4.17.

In a similar manner 3,4,5-trimethoxyphenyl2-(l-pyrrolidinyl)-l-cyclohexen-1-yl ketone [prepared from 0.1 mole of2-(3,4,5-trimethoxybenzoyl)cyclohexanone] was hydrogenated in ethanol inthe presence of 1 g. of 5% rhodium on alumina catalyst. Thehydrogenation continued for 30 hours. The mixture was then filtered,evaporated to dryness, and the residue was dissolved in ether andtreated with ethereal hydrogen chloride to give 5.2 g. of solid. Thissolid was recrystallized from isopropyl alcohol to give 4.6 g. ofa-(3,4,5-trimethoxyphenyl)-2-(l-pyrrolidinyl)cyclohexanemethanolhydrochloride of melting point 2l6-2l7 C.

Analysis.-Calcd. for C H NO -HCl (percent): C, 62.24; H, 8.36; CI, 9.19;N, 3.63. Found (percent): C, 62.31; H, 8.82; Cl, 9.15; N, 3.65.

EXAMPLE 5 8 3,4,5-trimellz0xy (2 piperidinocyclopentyI(benzyl alcohol [a(3,4,5 trimethoxyphenyl)-2-piperidinocyclopentanemethanol] (A)3,4,5-TRIMETI-IOXYPHENYL 2-PIPERIDINO- CYCLOPENTYL KETONE A solution of15.1 g. (0.1 mole) of l-piperidino-lcyclopentene was added, in anitrogen atmosphere, with ice cooling, to a solution of 10.1 g. (0.1mole) of triethylarnine in 42 ml. of chloroform (purified by passagethrough a column of basic alumina). To this solution was added asolution of 23.0 g. (0.1 mole) of 3,4,5-trimethoxybenzoyl chloride inml. of chloroform, over a period of 1.5 hours, while the temperature ofthe reaction mixture was kept at 510 C. The mixture was then stirredovernight at room temperature (22-25 C.) and was filtered to give 6.91g. of triethylamine hydrochloride. The filtrate was evaporated todryness at C. The residue was dissolved in 250 ml. of ethanol, 12 g.(0.2 mole) of acetic acid and l g. of platinum oxide were added andhydrogenation was carried out at an initial pressure of 51 pounds. Twomoles of hydrogen were taken up during 1 hour and 28 minutes; more thanof the calculated hydrogen was absorbed in the first half hour. Themixture was then filtered and evaporated to dryness. A mixture of ml. ofether and 100ml. of 10% aqueous hydrochloric acid Was added, and theobtained reaction mixture was stirred for 1.5 hours. The layers wereseparated and the aqueous layer was extracted once with ether. The etherextracts were washed with water to give the neutral layer. The acidiclayer was cooled in ice and basified with 20% aqueous sodium hydroxide.It was extracted twice with ether, the combined ether extract was washedwith water, saturated salt solution, dried by passage through anhydroussodium sulfate and evaporated to give 14.6 g. of a brown oil whichsolidified on standing in vacuo overnight. The solid was dissolved in150 ml. of petroleum ether (boiling ange between 30-60 C.) and 20 ml. ofether and cooled with ice for 2 hours. The resulting suspension wasdecanted, thus providing solid A and filtrate B. Filtrate B wasevaporated to about half the volume and cooled. The resulting solid, 1.2g. of melting point 130 C., was removed by filtration. Recrystallizationof this solid from ether gave colorless needles of melting point133.5l34.5 C. The melting point of this material was not changed byrecrystallization from ether. Ultraviolet, infrared and NMR spectra andalso carbon,

hydrogen and nitrogen analysis indicated that this product was amixture.

Solid A and the residue from filtrate B were combined to give 13.3 g. ofa yellow solid. This solid was dissolved in 50 ml. of benzene andchromatographed over 400 g. of neutral alumina, taking six benzenefractions of 250 ml. each. Fraction 2 contained 2.378 g. of materialwhich was crystallized from 20 ml. of Skellysolve B hexanes to give 1.5g. of 3,4,5-trimethoxyphenyl 2-piperidinocyclopentyl ketone of meltingpoint 7980 C.

Ultraviolet: 7 217 (29,400); 283 (10,700).

Analysis.-Calcd. for C H NQ; (percent): C, 69.13; H, 8.41; N, 4.03.Found (percent): C, 69.21; H, 8.58; N, 4.14.

The above neutral layer contained a solid fraction of 8.78 g. whichafter recrystallization from Skellysolve B hexanes gave 6.8 g. ofcyclopentyl 3,4,5-trimethoxyphenyl ketone of melting point 4647.5 C.

(B) 3,4,5-TRIMETHOXY-a-(Z-PIPERIDINOCYCLOPEN- TYL)BENZYL ALCOHOL Asolution of 1.2g. (3.48 mmoles) of 3,4,5-trimethoxyphenyl2-piperidinocyclopentyl ketone in 25 ml. of ether was added over aperiod of minutes to a solution of 1.2 g. of lithium aluminum hydride in100 ml. of ether, and the mixture was stirred for 21 hours. It was thendecomposed by successive addition of 1.2 g. of water, 1.2 ml. of aqueoussodium hydroxide and 3.6 ml. of water. The thus-obtained reactionmixture was stirred for a period of 2 hours giving a suspension. Thissuspension was filtered and the solid washed with ether. The etherwashing and the ether filtrate were combined, dried by passage throughanhydrous sodium sulfate and evaporated to give 1.2 g. of an oil. Theoil was chromatographed over 48 g. of Florisil (anhydrous magnesiumsilicate). Solution with five 100-ml. portions of a mixture consistingof 10% acetone and 90% Skellysolve B hexanes gave 0.136 g. of an oil.Elution with five portions of 100 ml. each of acetone-80% Skellysolve Bhexanes mixture gave 0.582 g. of oil. After standing in vacuo for oneweek, the oil crystallized to give a solid of melting point 85-88" C.This solid was recrystallized from ether-petroleum ether to give a 3,4,5trimethoxy-u-(2-piperidinocyclopentyl) benzyl alcohol melting at 9192 C.

Ultraviolet: sh. 224 (9,100); sh. 234; sh. 269 (849); sh. 278 (660).

Analysis.-Calcd. for C H NO (percent): C, 68.74; H, 8.94; N, 4.01. Found(percent): C, 68.49; H, 8.98; N, 4.25.

Further elution with 30% acetone-70% Skellysolve B hexanes (fiveportions of 100 ml. each) gave 0.140 g. and elution with 50% acetone-50%Skellysolve B hexanes mixture (five portions of 100 ml. each) gave 0.170g. of solids. A 75% acetone-% Skellysolve B hexanes mixture (fiveportions of 100 ml. each) gave 0.087 g. and elution with acetone (twoportions of 100 ml. each) gave 0.154 g. of solids. These solid fractionswere combined and recrystallized from petroleum ether (boiling range 60C.) to give 0.44 g. of crystals, which after recrystallization from a1:1 mixture of ether-petroleum ether (boiling range of petroleum ether3060 0), gave a material melting at 119-120 C. which was another isomerof 3,4,5-trimethoxy-u-(2-piperidinocyclopentyl)benzyl alcohol.

EXAMPLE 59 3,4,5-trimethoxy 0c (Z-pyrrolidinocylopentyl)benzyl alcohol[ad-(3,4,5 trimetlzoxyphenyl)-2-pyrr0lidin0-cyclopentanemethanol] Amixture of 8.35 g. (0.03 mole) of2-(3,4,5trimethoxybenzoyl)cyclopentananone, 6.5 g. (0.09 mole) ofpyrrolidine, 240 ml. of benzene and 0.2 g. of p-toluenesulfonic acid wasrefluxed under a nitrogen atmosphere for 21 hours using an azeotropicseparator; 0.5 m1. of water was collected. The solution was evaporatedto dryness,

3,4,5-trimethoxyphenyl 2 pyrrolidino-l-cyclopenten-l-yl ketone beingobtained as a residue. This residue was dissolved in 100 ml. of methanoland hydrogenated in the presence of 0.3 g. of platinum oxide at aninitial pressure of 5 4 pounds. One molar equivalent of hydrogen wastaken up over a period of 4 hours whereupon the hydrogenation wasstopped. The mixture was filtered through diatomaceous earth, and thefiltrate evaporated to dryness 3,4,5- trimethoxyphenyl2-pyrrolidinocyclopentyl ketone being obtained as a residue. One-half ofthis product (5 g.; 0.015 mole) was dissolved in 100 ml. of benzene.This solution was added during 10 minutes to a solution of 5 g. oflithium aluminum hydride in 200 ml. of ether, and the mixture wasrefluxed with stirring for a period of 3 hours. It was then decomposedby successively adding 5 m1. of water, 5 ml. of 15% aqueous sodiumhydroxide and 15 m1. of water. The suspension was filtered and the solidwashed with ether. The filtrate and the ether washings were combined,extracted with 10% hydrochloric acid (four portions of 50 ml. each) andthe acidic extracts were basified by the addition of aqueous sodiumhydroxide. The basified solution was extracted with four portions (each50 ml.) of methylene chloride. The methylene chloride extracts werecombined, washed with water, then with saturated salt solution, dried bypassage through anhydrous sodium sulfate and evaporated to give 4.5 g.of a yellow oil. This yellow oil was dissolved in 20 ml. of methylenechloride and chromatographed over 200 g. of Florisil (anhydrousmagnesium silicate). The elution was carried out with five portions of200 ml. each of 50% acetone-50% Skellyslove B hexanes. The eluates wereconcentrated to give 0.4 g. of solid which was recrystillized fromSkellysolve B hexanes to give 3,4,5-trimethoXy-a-(2-pyrrolidinocyclopentyl)benzyl alcohol of melting points 86 C.

Ultraviolet: sh. 227 (9,300); x 269 (788); sh. 278 (573). NMR showed Hon carbon bearing the OH as a doublet centered at 316.5 cps. (j:3 cps).

AnaIysis.Calcd. for C H NO (percent): C, 68.03; H, 8.71; N, 4.18. Found(percent): C, 67.50; H, 8.73; N, 4.43.

Elution of the above column with five portions of 200 ml. each ofacetone gave after evaporation 0.58 g. of a solid, which wascrystallized from ether and thereupon from tetrahydrofuran-Skellyslove Bhexanes to give isomeric 3,4,5-trimethoxy a (2 pyrrolidinocyclopentyl)benzyl alcohol of melting point l47l48 C.

Ultraviolet: sh. 225 (8,950); a 270 (1,100); sh. 227 (567). NMR showed Hon carbon bearing the OH as a doublet centered at 291 cps. (j:5 cps.).

Alzalysis.Calcd. for C H NO (percent); C, 68.03; H, 8.71; N, 4.18.(Found (percent): C, 67.70; H, 8.90; N, 4.25.

EXAMPLE 60 p-Ethoxyphenyl 2-piperidin0-1-cycl0hexen-l-yl ketone In themanner given in Example 31, 2-(p-ethoxybenzoyl)cyclohexanone was reachedwith a piperidine in the presence of p-toluenesulfonic acid to givep-ethoxyphenyl Z-piperidino-l-cyclohexen-l-yl ketone.

EXAMPLE 61 p-Benzyloxyphenyl Z-pyrrolz'dino-I-cycl0hexenl-yl ketone Inthe manner given in Example 31, 2-(p-benzyloxybenzoyl)-cyclohexanone wasreacted with pyrrolidine in the presence of p-toluenesulfonic acid togive p-benzyloxyphenyl 2-pyrrolidino-l-cyclohexen-l-yl ketone.

EXAMPLE 62 p-Benzyloxyphenyl Z-piperidino-I-cycl0hexen- I-yl ketone Inthe manner given in Example 31, 2-(benzyloxybenzoyl)-cyclohexanone wasreacted with piperidine in the presence of p-toluenesulfonic acid togive p-benzoyloxyphenyl 2-piperidino-l-cyclohexen-l-yl ketone.

29 EXAMPLE 63 p-(2-hydr0xyeihoxy phenyl Z-pi perz'di110-2-cycl0-lzexen-I-yl kctone In the manner given in Example 31,2'[p-(2-hydroxyethoxy)-benzoyl]-cyclohexanone was reacted withpiperidine in the presence of p-toluensulfonic acid to give p-(2-hydroxyethoxy)phenyl 2 piperidino-l-cyclohexene-l-yl ketone.

EXAMPLE 64 o-Methoxypllenyl 2piperidin0-l-cycIo/zexen-J-yl kerone In themanner give in Example 31, 2-(o-meth0xybenzoyl)cyclohexanone was reactedwith piperidine in the presence of p-toluenesulfonic acid to giveo-methoxyphenyl 2-piperidino-l-cyclohexen-l-yl ke-tone.

EXAMPLE 65 -Hydr0wyphenyl 2-piperidin0-1cycl0hexen-1-yl ketone In themaner given in Example 31, Z-(o-hydroxybenzoyl)cyclohexanone was reactedwith piperidine in the presence of p-toluenesulfonic acid to giveo-hydroxyphenyl Z-piperidino-l-cyclohexen-l-yl ketone.

EXAMPLE 65A p-Hydroxyphenyl 2-piperidi/z0-1-cycl0hexen-]-yl ketone Inthe manner given in Example 31, 2-(p-hydroxybenzoyl)cyclohexan0ne wasreacted with piperidine in the presence of p-toluenesulfonic acid togive phydroxyphenyl l-piperidino-1-cyclohexen-1-yl ketone.

EXAMPLE 66 2-meth0xy-4-methylphenyl Z-piperidz'no-I-cyclohexen-I-ylketone In the manner given in Example 31, 2-(2-meth0xy-4-methylbenzoyl)cyclohexanone was reacted with piperidine in the presenceof p-toluenesulfonic acid to give 2-methoxy-4-methylphenyl 2-piperidino1 cyclohexen-l-yl ketone.

EXAMPLE 67 3 ,5 -dimethyl-4-meth0xyphenyl 2-piperidin0-1-cyclohexen-I-ylketone In the manner given in Example 31, 2-(3,5-dimethyl-4-rnethoxybenzoyl)cyclohexanone was reacted with piperidine in thepresence of p-toluenesulfonic acid to give 3,5-dimethyl-4-methoxyphenyl2-piperidino-1-cyclohexen- 1-yl ketone.

EXAMPLE 68 p-Trifluoromethylphenyl Z-piperidino-I-cycl0hexen- I-ylketone In the manner given in Example 31,Z-(p-trifiuoromethylbenz0yl)-cyclohexanone was reacted with piperidinein the presence of p-toluenesulfonic acid to givep-trifluoromethylphenyl Z-piperidino-l-cyclohexen-l-yl ketone.

EXAMPLE 69 p-Allyloxyphenyl Z-piperidino-I-cycl0hexen-1-yl ketone In themanner given in Example 31, Z-(p-allyloxybenzoyl)cyclohexanone wasreacted with piperidine in the presence of p-toluenesulfonic acid togive p-allyloxyphenyl Z-piperidino-l-cyclohexen-l-yl ketone.

EXAMPLE 70 p-(Methylcarbamoyloxy )pherzyl 2piperidin0-]- cyclohexen-l-ylketone In the manner given in Example 31,Z-[p-(methylcarbamoyloxy)benzoyl]cyclohexanone was reacted withpiperidine in the pnesence of p-toluenesulfonic acid to givep-(methylcarbamoyloxy)phenyl 2 piperidino-l-cyclohexen-l-yl ketone.

30 EXAMPLE 71 3 ,4 -meth ylen ed ioxy phenyl 2- hexahydro-I H -azepin- 1-y[ -I-cycl0lzexen-l -yl ketone In the manner given in Example 31,2-(3,4-methylenedioxybenzoyl)cyclohexanone was reacted withhexamethyleneimine in the presence of p-toluenesulfonic acid to give3,4-methylenedioxyphenyl Z-(hexahydro-lH-azepin- 1-yl)-l-cyclohexen-l-ylketone.

EXAMPLE 72 p-C/zlorop/zenyl 2-(2is0pr0pyIpyrrolidino) -1-cyclohexen-1-yl ketone In the manner given in Example 31Z-(p-chlorobenzoyl)cyclohexanone was reacted with 2-isopropylpyrrolidinein the presence of p-toluenesulfonic acid to give p-chlorophenyl 2(2-isopropylpyrrolidino)-1-cyclohexenl-yl ketone.

EXAMPLE 7J3 p-Hydroxyphenyl 2-0ctamethyleneimino-1-cycl0hexen- J-ylketone o-methylphenyl Z-pyrrolidino-l-cyclohexen-l-yl ketone;

p-methylphenyl 2-pyrrolidino-l-cyclohexen-1-yl ketone;

2-methoxy-4-methylphenyl 2-m0rpholino-l-cyclohexenl-yl ketone;

Z-hydroxy-S-chlorophenyl 2-homom0rpholino-1-cyclohexen-l-yl ketone;

p- (carboxyrnethoxy) phenyl 2-3,6-dimethylhexamethyleneimino)-1-dyclohexen-1-yl ketone;

3,4-methylenedioxyphenyl 2- (2-methylpiperidino)-1- cyclohexene-l-ylketone;

p-ethoxyphenyl 2-pyrrolidino-l-cyclohepten-l-yl ketone;

2,3,4-trimethoxyphenyl Z-piperidino-l-cycloocten-l-yl ketone;

3 ,5 -diiodophenyl 2-( 3-methylpiperidino -l-cyclohexen- 1-yl ketone;

2-methoxy-4-chlorophenyl 2-piperidino-I-cyclohexen- 1-yl ketone;

Z-methyl-4-triflu0romethylphenyl Z-piperidino-l-cyclohexen-l-yl ketone;

3,4-dipropylphenyl 2-pyrrolidino-l-cyclohepten-l-yl ketone;

2,5-dichlorophenyl Z-(hexahydro-1H-azepin-1-yl)-1- cyclohepten-l-ylketone;

3 ,4-dichlorophenyl 2- (3-methylpiperidino -1-cycloocten- 1-yl ketone;

p-propoxyphenyl 2- (4-butylpiperazino) -1-cyc1ooctenl-yl ketone;

2,5-diiodophenyl 2-(Z-methylhexarnethyleneimino)-1- cyclohepten-l-ylketone;

3-fluoroph eny1 Z-pyrrolidino-1-cyclopenten-l-yl ketone;

2-hexylphenyl Z-piperidino-1-cycl0penten-l-yl ketone;

3-pentylphenyl Z-piperidino-l-cyclo'hexen-l-yl ketone;

Z-butylphenyl 2-morpholino-l-cyclohexen-l-yl ketone;

Z-propylphenyl 2-(1,2,3,3,4-tetrahydro-1-quinolyl)-lcyclohepten-l-ylketone;

3-ethylphenyl Z-piperidino-1-cycloocten-lyl ketone;

Z-methoxy-S-bromophenyl 2-pyrrolidino-l-cyclopentenl-yl ketone;

phenyl 2-octamethyleneiminol-cycloocten-l-yl ketone;

phenyl 2-(2,3,6-trimethylmorpholine)-l-cycloheptenl-yl ketone;

and the like.

31 EXAMPLE 74 a-(p-Ethoxyphenyl) 2pipedidinocycl0hexanemethanolhydrochloride In the manner given in Example 32, p-ethoxyphenylZ-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presenceof platinum oxide to give a-(p-ethoxyphenyl) 2piperidinocyclohexanemethanol recovered as hydrochloride; melting point221-222 C.

EXAMPLE 75 w (p-benzoyloxyphenyl -2-pyrr0lidinocyclohexanemethanol Inthe manner given in Example 32, p-benz'yloxyphenyl2-pyrrolidino-l-cyclohexen-l-yl ketone was hydrogenated in the presenceof platinum oxide to give a-(p-benzyloxyphenyl)-2-pyrrolidinocyclohexanemethanol.

EXAlMPLE 76 Cis-A-a- (p-benzyloxyphenyl -2-piperidinocycl0hexanemethanolIn the manner given in Example 32, p-benzyloxyphenylZ-piperidino-l-cyclohexen-1-yl ketone was hydrogenated in the presenceof platinum oxide to give cis-A-a-(p-benzyloxyphenyl)-2-piperidinocyclohexanemethanol of melting point148.5l49.5 C.

In the same manner, catalytic hydrogenation of cis-pbenzyloxyphenylZ-piperidinocyclohexyl ketone (Example 88) gives the same product.

EXAMPLE 7 6A Cis-B-m w-benzyloxyphenyl)-2-piperidinocyclohexanemethanoland hydrochloride thereof In the manner given in Example 47, cis-A-a-(p-benzyloxyphenyl) 2 piperidinocyclohexanemethanol was converted bymeans of trifluoroacetic acid to cis-B-a-(pbenzyloxypheriyl)-2-piperidinocyclohexanemethanol of melting point 129-l30C.

This base was treated with ethereal hydrogen chloride, to obtain cis-B-u-(pbenzyloxyphenyl)piperidinocyclohexanemethanol hydrochloride ofmelting point 238- 240 C.

EXAMPLE 77 a-[p-(2-hydroxyethoxy)phenyl]-2-piperidinocyclohexanemethanolhydrochloride EXAMPLE 78 a(o-Methoxyphenyl),2-piperidinocyclhexanemethanol hydrochloride In themanner given in Example 32, o-methoxyphenyl2-piperidino-l-cyclohexen-1-yl ketone was hydrogenated in the presenceof platinum oxide to givea-(o-methoxyphenyl)-2-piperi'dinocyclohexanemethanol recovered ashydrochloride.

EXAMPLE 79 a- 0-H ydroxy ph enyl -2-p i pev'idinocyclohexanemethanol Inthe manner given in Example 32, o-hydroxyphenylZ-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presenceof platinum oxide to give zx-(O-hYdIOXY- 32 phenyl) 2piperidinocyclohexanemethanol of melting point 122 122.5 c.

The above compound is useful as a diuretic.

EXAMPLE 79A Cis A a-(p-hydroxyphenyl)-2-piperidinocyclohexanemethanoland hydrochloride thereof In the manner given in Example 32,p-hydroxyphenyl 2-piperidino-l-cyclohexen-l-yl ketone was hydrogenatedin the presence of platinum oxide to givecis-A-a-(p-hydroxyphenoyl)-2-piperidinocyclohexanemethanol of meltingpoint l79-180 C.

This base was treated with ethereal hydrogen chloride to obtaincis-A-a-(p-hydroxyphenyl)-2-piperidinocyclohexanemethanol hydrochlorideof melting point 204- 204.5 C.

These above compounds are useful as diuretics.

EXAMPLE 79B Cis B a-(p-hydroxyphenyl)-2-piperidinocyclohexanemethanol Inthe manner given in Example 47,cis-A-a-(p-hydroxyphenyl)-2-piperidinocyclohexanemethanol was convertedby means of trifluoroacetic acid to ClS-B-oc-(P-hYdI'OXY-phenol)-2-cyclohexanernethanol of melting point 182- 183 C.

The above compound is useful as a diuretic.

EXAMPLE 80 a (2-methoxy-4-methylphenyl)-2-piperidinocyclohexanemethanolhydrochloride In the manner given in Example 32, 2-methoxy-4-methylphenyl Z-piperidino-l-cyclohexene-l-yl ketone was hydrogenated inthe presence of platnium oxide to give a(2-methoxy-4-methylphenyl)-2-piperidinocyclohexanemethanol recovered ashydrochloride; melting point 215252 C.

EXAMPLE 81 a (3,5dimethyl-4-methoxyphenyl)-2-piperidinocyclohexanemethanol hydrochlorideIn the manner given in Example 32, 3,5-dimethyl-4- methoxyphenyl 2piperidino l-cyclohexen-l-yl ketone was hydrogenated in the presence ofplatinum oxide to give oc- 3,5 -dimethyl-4-methoxyphenyl)-2-piperidinocyclohexanemethanol recovered as hydrochloride.

EXAMPLE 82 a-(p Trifluoromethylp'henyl) Z-piperidinocyclohexanemethanolhydrochloride In the manner given in Example 32, p-trifluoromethylphenyl2-piperidino-l-cyclohexen-l-yl ketone was .hydrogenated in the presenceof platinum oxide to give a-(ptrifluoromethylphenyl)2-piperidinocyclohexanemethanol recovered as hydrochloride.

EXAMPLE 83 a (p-Propoxyphenyl)-2-piperidinocyclohexanemethanolhydrochloride In the manner given in Example 32, p-allyloxyphenylZ-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presenceof platinum oxide to givea-(p-propoxyphenyl)-2-piperidinocyclohexanemethanol recovered ashydrochloride.

EXAMPLE 83A Cis A a (p-allyloxyphenyl)-2-piperidinocyclohexanemethanol Amixture of 11.6 g. (0.04 mole) ofcis-A-a-p-hydroxyphenyl)-2-piperidinocyclohexanemethanol and 1.8 g. of a53.3% mineral oil dispersion of sodium hydride (0.04 mole of sodiumhydride) in ml. of dimethyl sulfoxides was stirred for a period of 1hour. A solution of 4.9 g.

(0.0404 mole) of allyl bromide in 15 ml. of ether was added to themixture above during a period of 15 minutes and the obtained reactionmixture was stirred for 3 hours at room temperature and then poured in ll. of ice water. A white solid separated which was extracted three timeswith ether. The ether extracts were combined, washed with water andsaturated sodium chloride solution, dried over anhydrous sodium sulphateand evaporated to give a residue. This residue was twice recrystallizedfrom ether-pentane to give a total of 11.8 g. (89%) of CiS-A-a-(p-allyloxyphenyl) 2-piperidinocyclohexanemethanol of melting point70-72 C.

Analysis.Calcd. for C H NO (percent): C, 76.55; H, 9.48; N, 4.25. Found(percent): C, 76.79; H, 9.10; N, 4.20.

The above compound is useful as an oral antidiabetic agent.

EXAMPLE 84 a [p- (Mefhylcarbamoyloxy)phenyl]-2piperidin0cycl0-hexanemethanol hydrochloride In the manner given in Example 32,p-(methylcarbamoyloxy)-phenyl Z-piperidino-1-cyclohexene-1-yl ketone washydrogenated in the presence of platinum oxide to giveot-[p-(methylcarbamoyloxy)phenyl]-2-piperidinocyclohexanemethanolrecovered as hydrochloride.

EXAMPLE 85 a (3,4 methylenedioxphenyl)-2-piperidin0cyclohexanemethanolhydrochloride In the manner given in Example 32,3,4-methylenedioxyphenyl Z-piperidino-1-cyclohexene1-yl ketone washydrogenated in the presence of platinum oxide to give a-(3,4-methylenedioxyphenyl) Z-piperidinocyclohexanemethanol recovered ashydrochloride.

EXAMPLE 86 a (p Cliiorophenyl)2-(2-isopropylpyrrolidino)cyclohexaizcmethanol hydrochloride In themanner given in Example 32, p-chlorophenyl 2-.(2-isopropylpyrrolidino)-1-cyclohexene-1-yl ketone was hydrogenated inthe presence of platinum oxide to give or (p chlorophenyl)2-(2-isopropylpyrrolidino)cyclohexanemethanol recovered ashydrochloride.

EXAMPLE 87 t (p Hydroxyphenyl)-2-0ctamethyleneiminocyclohcxancmelhanolhydrochloride In the manner given in Example 32, p-hydroxyphenyl2-octamethyleneimino-l-cyclohexene-1-yl ketone was hydrogenated in thepresence of platinum oxide to give oc- (p hydroxyphenyl)2-octamethyleneiminocyclohexanemethanol recovered as hydrochloride.

In the same manner given in Example 32, hydrogenating other ketocompounds of Formula II in the presence of platinum oxide gives thesubstituted methanols of the Formula IV recovered as hydrochlorides.Representative hydrochlorides, thus obtained, include: thehydrochlorides of Ot- (o-methylphenyl -2-pyrrolidinocyclohexanemethanol;

ot-(p-methylphenyl 2-pyrrolidinocyclohexanemethanol;

u- 2-meth0xy-4-methylphenyl -2-morpholinocyclohexanemethanol;

w 2hydroxy-S-chlorophenyl -2-homomorpholinocyclohexanemethanol;

or- [p- (carboxymethoxy phenyl] -2- 3 ,6-dimethylhexamethyleneiminocyclohexanemethanol;

a- 3 ,4-methylenedioxyphenyl) -2- Z-methylpiperidino) cyclohexanemethanol;

oc- (p-ethoxyphenyl -Z-pyrrolidinocycloheptanemethanol;

a- 2, 3 ,4-trimethoxy phenyl -2-pi peridinocyclooctanemethanol;

w (3 ,5-d iiodophenyl -2- 3-methylpiperidino cyclohexanemethanol;

Ot- Z-methyl-4-trifluoromethylphenyl -2-piperidinocyclohexanemethanol;

zx- (3 ,4-dipropylphenyl -2-pyrrolidinocycloheptanemethanol;

w 2,5 -dichlorophenyl -2- (hexahydro- 1 H-azepinl-ylcycloheptanemethanol;

et- 3 ,4-dichlorophenyl -2- 3 -methylpiperidin0 cyclooctanemethanol;

0cp-propoxyphenyl -2- (4-butylpiperazino cyclooctanemethanol;

Ot- 2,5 -diiodophenyl -2- 2-methyll1examethyleneiminocycloheptanemethanol;

er-( 3-fluorophenyl -2-pyrrolidinocyclopentanemethanol;

OL- Z-hexylphenyl) -2-piperidinocyclopentanemethanol;

a-( 3-pentylphenyl) -2-piperidinocyelohexanemethanol;

OL- Z-butylphenyl -2-morpholinocyclohexanemethanol;

a-(2-propylphenyl)-2-( 1,2,3 ,4tetrahydrol-quinolyl)cycloheptanemethanol;

Ot- 3-ethylphenyl -2-piperidinocyclooctanemethanol;

Dt- 2-rnethoxy-5-brornophenyl -2-pyrrolidinocyclopentanemethanol;

tx-phenyl-2-octamethyleneiminocyclooctanemethanol;

a-phenyl-Z- (2,3 ,6-trimethylmorpholino cycloheptanemethanol;

and the like.

EXAMPLE 88 Cis-p-bcnzyloxyphelzyl Z-piperirlinocyclohcxyl ketone In themanner given in Example 39, p-benzyloxyphenylZ-piperidino-l-cyclohexen-l-yl ketone dissolved in ethan01 washydrogenated in the presence of platinum oxide until one molarequivalent of hydrogen Was consumed (42 minutes) to giveeis-p-benzyloxyphenyl 2-piperidinocyclohexyl ketone of melting point87.588.5 C.

Analysis.Calcd. for C H NO (percent): C, 79.53; H, 8.28; N, 3.71. Found(percent): C, 78.88; H, 8.27; N, 3.65.

In the same manner given in Example 39, selective catalytic reduction(preferably with platinum oxide) of other compounds of Formula IIproduces cis-ketones of Formula III, e.g., cis-3,4,5-trimethoxyphenyl2-piperidinocyclohexyl ketone; cis-p-ethoxyphenyl 2-piperidinocyclohexylketone; cis-p-(2-hydroxyethoxy)phenyl 2-piperidinocyclohexyl ketone;cis-p-trifluoromethylphenyl 2-piperidinocyclohexyl ketone;cis-p-chl0ropheny1 2-(2-isopropylpyrrolidino)cyclohexyl ketone;cis-3,4-methylenedioxyphenyl 2-(hexahydro-1H-azepin 1 yl)cyclohexylketone; cis-2,3,4-tri1nethoxyphenyl Z-piperidinocyclooctyl ketone;cis-3,4-dichlorophenyl 2-(3-methylpiperidino)cyclooctyl ketone;cis-2,5-dichlorophenyl 2-(hexahydro-lH- azepinyl-l-yl)cycloheptylketone; and the like.

In the manner given in Example 41, other cis-alcohols can be obtained byhydrogenating a compound of Formula II or III in the presence of acatalyst such as platinum oxide, palladium or the like. Representativecompounds thus obtained include: cis-a-(p-methylphenyD-2-piperidinocyclohexanemethanol, melting point 102- 103 C., ashydrochloride melting point 251-253 C.;cis-a-(p-methoxyphenyl)-2-(4-methyl 1 piperazinyl)cyclohexanemethanol,melting point 132-133 C.; cis-a-(pmethoxyphenyl) 2 (4methylpiperidino)cyclohexanemethanol, melting point 93-94 C.;cis-a-(p-methoxyphenyl)-2-morph0linocyclohexanemethanol, melting pointIll-112 C.; eis-et-(p-methoxyphenyl) 2 (3azabicycl0[3.2.2]nonan3-yl)cyclohexanemethanol, melting point 114.5115.5 C.; cis-a-(p-methox yphenyl)-2-pyrrolidinocyclohexanemethanol,melting point 146147 C.; cis-a- (p-methoxyphenyl) 2 (2methylpiperidino)cyclohexanemethanol, as perchlorate, melting point 108-111 C.;cis-ot-(p-methoxyphenyl)-3,3-dimethyl-6-piperidinocyclohexanemethanol,melting point 133-135" C.; cis-m-(4-methoxy-3,S-dimethylphenyl) 2(hexahydrolH-azepin-l-yl)cyclohexanemethanol, as hydrochloride, meltingpoint 247-248" C.; cisx-(2,4-dimethylphenyl)-2-piperidinocyclohexanemethanol, as hydrochloride, melting point 239-240C.;cis-a-(2,5-dichlorophenyl)-2-heptamethyleneiminocyeloheptanemethanol;CiS-a-(Z butylphenyl) -2-morpholinocyclohexanemethanol; CiS-oc-(2-propylphenyl) 2 (1,2,3,4-tetrahydro-l-quinolyl)cycloheptanemethanol;cis-u-(2,3,4-trimethoxyphenyl) 2 piperidinocyclooctanemethanol; and thelike.

EXAMPLE 89 1-[2-(u,3,4,5-tetrameth0ucybenzyl cyclohexyl] pipcridinehydrochloride (isomer cis-A hydrochloride) A solution of 4 g. (0.01mole) of a-(3,4,5-trimethoxy phenyl)-2-piperidinocyclohexanemethanolhydrochloride in 160 ml. of water was basified by adding sufficient 10%aqueous sodium hydroxide solution. This solution was extracted threetimes with 100 ml. of methylene chloride. The methylene chloridesolution was evaporated, leaving an oily free base.

A solution of the free base a-(3,4,5-trimethoxyphenyl)-2-piperidinocyclohexanemethanol in 25 ml. of ether was added to 100 ml.of liquid ammonia containing 0.01 mole of sodium amide and the mixturewas stirred for a period of 50 minutes, while cooling in DryIce-acetone. A solution of 1.42 g. (0.01 mole) of methyl iodide in ml.of ether was then added during 5 minutes; the Dry Ice bath was removedand the mixture allowed to stir at room temperature for a period of 7hours. It was then allowed to evaporated overnight (about 20 hours). Tothis reaction mixture was then added 50 ml. of water, and the mixturewas extracted with three portions of 50 ml. each of methylene chloride.The combined methylene chloride extracts were washed with water,saturated salt solution, dried by passing through anhydrous sodiumsulfate and evaporated, to give 3.6 g. of an oily product. The oil wasdissolved in methylene chloride and chromatographed on 108 g. ofFlorisil (anhydrous magnesium silicate). The column of Florisil waseluted with four portions, each 200 ml., of a 3% acetone 97% SkellysolveB hexanes solution, yielding 1.80 g. of an oil after evaporation of thesolvents. The oil was dissolved in ether and treated with etherealhydrogen chloride to give 1.4 g. of material melting at 2272-'28 C. Thismaterial was recrystallized from methanol-ether to give 1-[2-(oc,3,4,5tetramethoxybenzyl)cyclohexyl]piperidine hydrochloride (isomer cis-Ahydrochloride) of melting point 224225 C.

Ultraviolet: Max, 212 (33,400); sh. 235 (6,600); 271 (923);sh. 279(646).

Analysis.Calcd. for C H NO -HCl (percent): C, 63.82; H, 8.77; Cl, 8.56;N, 3.38. Found (percent): C, 63.70; H, 8.95; Cl, 8.25; N, 3.46.

EXAMPLE 90 Cis-B-1- [2-( a,p-dimethoxybenzyl cycloh exyl] piperidine andhydrochloride thereof (A) A solution of cis-A-u-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (3.0 g.; 0.01 mole) in 50 ml. of methanolwas treated with a solution of 5 g. of hydrogen chloride in 50 ml. ofmethanol, and an additional 100 ml. of methanol was added. The solutionwas allowed to stand for 18 hours at about 25 C. and was then evaporatedto dryness at 45 C. under reduced pressure. The oily residue wasdissolved in 50 ml. of water; the solution was basified with aqueoussodium hydroxide solution and extracted with ether. The extract waswashed with water, then with saturated sodium chloride solution, driedthrough anhydrous sodium sulfate, and evaporated to dryness, to obtain3.0 g. (95% yield of cis-B-l[2-a,pdimethoxybenzyl)cyclohexyl]piperidineof melting point 36 75-77" C. Recrystallization from ethanol gave 2.3 g.of this compound, melting point 81-82 C.

Ultraviolet: k 226 (13,200); 275 (1,460); 282 (1,210).

Analysis.Calcd. for C 'H NO (percent): C, 75.67; H, 9.84; N, 4.41. Found(percent): C, 75.70; H, 10.06; N, 4.15.

A solution of 10.7 g. (0.0354 mole) ofcis-B-1-[2-(u,pdimethoxybenzyl)cyclohexyl]piperidine in ml. of ether wastreated with 40 ml. of 1.3 N ethereal hydrogen chloride solution. Theresulting solid was crystallized from 25 ml. of methylene chloride and50 ml. of ether to give 9.3 g. ofcis-B-l-[2-(a,p-dimethoxybenzyl)cyclohexyl] piperidine hydrochloride ofmelting point 209 211 C.

Ultraviolet: A 227 (12,500); 275 (1,400); 281 (1,200).

Almlysis.Calcd. for cgoHg Noz'H'cl (percent): C, 67.87; H, 9.11; Cl,10.02; N, 3.96. Found (percent): C, 67.41; H, 9.31; CI, 10.47; N, 3.83.

(B) In the manner given in Example 89, an ether solution ofcis-B-u-(p-methoxyphenyl) 2 piperidinocyclohexanemethanol was treated inliquid ammonia with sodium amide and methyl iodide. Thecis-B-1-[2-(a,pdimethoxybenzyl)cyclohexyl]piperidine thus obtained wasidentical with the compound prepared by the above methanol-hydrogenchloride etherification procedure.

EXAMPLE 91 Cis-B-J [2-(u,p-dimetl10xybenzyl)cyclohexyl] piperidineN-oxide hydrate To an ice-cooled solution of 2.2 g. (7 mmoles) of cis-B-l-[2-(u,p-dimethoxybenzyl)cyclohexylJpiperidine in 50 ml. of methanolwas added 2.4 g. (14 mmoles) of mchloroperbenzoic acid. The resultingcolorless solution was allowed to stand in ice for 6 hours and then atroom temperature (23 to 25 C.) for about 18 hours. It was evaporated todryness at 35 C. to give an oily residue. To this residue was added 25ml. of water followed by 25 ml. of 5% aqueous sodium hydroxide, and thenthe mixture was extracted three times with a total of 100 ml. ofmethylene chloride. The methylene chloride extracts were combined,washed twice with saturated salt solution, dried by passage throughanhydrous sodium sulfate and evaporated to give 2.5 g. of an oil. Theoil was dissolved in 25 ml. of hot ethyl acetate (saturated with water),and the cloudy solution was filtered through a sinter funnel. Theresulting clear solution was evaporated to 10 ml., cooled and seeded.The resulting crystals were recovered by filtration and washed withether to give colorless prisms of cis-B-l- [2- a,p-dimethoxybenzylcyclohexyl] piperidine N-oxide hydrate melting at 108110 C.

Ultraviolet: A 227 (12,750); 275 (1,400); 282 (1,250).

Analysis.Calcd. for C H NO -H O (percent): C, 68.34; H, 9.46; N, 3.99.Found (percent): C, 68.66; H, 9.46; N, 3.96.

EXAMPLE 92 Cis-B-J [2- a,p-dimeth0xybenzyl cyclohexyl] piperidine andits methiodide A solution of 4 ml. of butyl lithium (0.01 mole) inhexane was added during 2 minutes to a solution of 0.03 g. (0.01 mole)of cis-B-a-(p-methoxyphenyl)-2-piperidino cyclohexanemethanol in 30 ml.of purified tetrahydrofuran. The mixture was stirred at room temperaturefor 30 minutes and then cooled in a Dry Ice bath at C. To this solutionwas added a solution of methyl iodide (1.42 g.; 0.01 mole) in 10 ml. oftetrahydrofuran, dropwise, over a period of 10 minutes. The mixture wasstirred at 70 C. for a period of 1.5 hours and then at room temperaturefor 19 hours. To the solution was thereupon added water (50 ml.) and thesolution was then extracted with three portions of ml. each of methylenechloride. The organic extracts were combined, dried by passage throughanhydrous sodium sulfate and evaporated to give 2.7 g. of crude product.The crude product was dissolved in 20 ml. of methylene chloride andchromatographed over 135 g. of neutral alumina. The material was firsteluted with eight portions of 250 ml. of a ether95% Skellysolve Bhexanes solution. After evaporation of the combined eluates, 1.523 g. ofsolid material, melting between 82-84 C., was obtained. Further elutionwith two portions of 250 ml. of 25% ether-75% Skellysolve B hexanes,with two portions of 250 ml. each of 50% ether-50% Skellysolve B hexanesand with two portions of 250 ml. each of 75% ether25% Skellysolve Bhexanes gave a total of 0.204 g. of solid material after evaporation ofthe combined eluates. The above fractions were all combined andrecrystallized from ethanol to give 0.644 g. of cis-B-l-[Z-u,p-dimethoxybenzyl cyclohexyl piperidine of melting point 8485.5 C.This free base was identical with the free base obtained in Example 90,parts A and B.

Further elution of the column with 250 ml. of methanol gave 1.446 g. ofmaterial which was crystallized from methanol-ether overnight in therefrigerator to give 0.252 g. of the methiodide ofcis-B-l-[2-(a,p-dimethoxybenzyl) cyclohexyl]piperidine, melting afteranother recrystallization from methanol-ether at 217-218 C.

Ultraviolet: A 223 (24,000); 275 (1,390); 281 (1,280).

Analysis.Calcd. for C H INO (percent): C, 54.90; H, 7.46; I, 27.63; N,3.05. Found (percent): C, 55.03; H, 7.68; I, 27.63; N, 3.23.

EXAMPLE 92a Cis-A -1- [2(or-p-dimethoxybeizzyl) cyclohexyl] piperidinehydrochloride methanol solvate In the manner given in Example 89, anether solution of cis-A-m-(p-methoxyphenyl)Z-piperidinocyclohexanemethanol was treated with a solution of sodiumamide in liquid ammonia and thereupon with a solution of methyl iodidein ether at about 70 C. to givecis-A-1-[2-(ix,pdimethoxybenzyl)cyclohexyl1piperidine recovered ashydrochloride methanol solvate of melting point 196.5-

Ultraviolet: 227 (11,400); 274 (1,380); 281 (1,200).

Analysis.Calcd. for C H NO -CH OH-HCI (percent): C, 65.34; H, 9.40; Cl,9.19; N, 3.63. Found (percent): C, 65.50; H, 9.28; Cl, 8.50; N, 4.03.

EXAMPLE 93 Trans-C-I- [2-(a,p-dfmethoxybenzyI) cyclolzaryl] piperidiizeA solution of butyl lithium in hexane (5.25 ml., containing 0.01 mole)was added during a period of minutes to a solution ofot-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (3.03 .g.; 0.01mole of the trans-C-alcohol) in 40 ml. of tetrahydrofuran in a nitrognatmosphere. The reaction mixture was then stirred for 45 minutes. It wascooled to -70 C. and thereto was added a solution of 1.41 g. (0.01 mole)of methyl iodide in 10 ml. of purified tetrahydrofuran over a period of30 minutes. The mixture was then stirred at room temperature (about C.)overnight for about 16 hours. The reaction mixture was thereuponevaporated to dryness and the resulting residue was dissolved in 50 ml.of water and 50 ml. of methylene chloride. The aqueous layer wasextracted with methylene chloride and the methylene chloride extractscombined, washed with saturated salt solution, dried by passage throughanhydrous sodium sulfate and evaporated,

to give 3.2 g. of a crude product. The crude product was chromatographedover 155 g. of neutral alumina, using six portions of 150 ml. each of 6%ether-94% Sltellysolve B hexanes solution. The eluates were evaporatedto give 1.642 g. of an oily product which was crystallized from 5 ml. ofmethanol to give 1.2 g. of a product melting at 78-79 C. Additionalrecrystallization gave pure trans- C1-[2-(a,p-dimethoxybenzyl)cyclohexyl1piperidine of melting point 7980 C.

Ultraviolet: A 225 (11,550); sh. 265 (1,150); 275 (1,550); 282 (1,350).

Analysis.Calcd. for C H NO (percent): C, 75.67; H, 9.84; N, 4.41. Found(percent): C, 75.80; H, 10.08; N, 4.71.

The same product was obtained when trans-C-a-(pmethoxyphenyl) 2piperidinocyclohexanemethanol in methanol solution was treated withanhydrous hydrogen chloride in methanol solution and the resultinghydrochloride was treated with 20% aqueous sodium hydroxide.

EXAMPLE 94 A hexane solution of butyl lithium (5.25 ml.; 0.01 mole) wasadded during 10 minutes to a solution of trans- D-a-(p-methoxyphenyl)Z-piperidinocyclohexanemethanol (3.03 g.; 0.01 mole) in 30 ml. ofpurified tetrahydrofuran in a nitrogen atmosphere. The mixture wasstirred for a period of 40 minutes, then cooled to C. and a solution of1.42 (0.01 mole) of methyl iodide in 10 ml. of purified tetrahydrofuranwas added over a period of 30 minutes. The mixture was then stirred for18 hours at room temperature, evaporated to dryness and the residuedissolved in 50 ml. of water and 50 ml. of methylene chloride. Theaqueous layer was extracted with methylene chloride and the combinedmethylene chloride extracts were washed with saturated salt solution,dried through sodium sulfate and evaporated. The crude product,amounting to 3.2 g., was chormatographed over g. of neutral aluminausing five fractions of ml. each of 6% ether94% Skellysolve B hexanes.The five fractions were combined and evaporated to give 1.145 g. of oilytrans-D 1 [2(a,p-dimethoxybenzyl)cyclohexyl] piperidine.

Ultraviolet: a 228 (12,350); 278 (1,550); 284 (1,300).

Analysis.-Calcd. for C H N'D (percent): C, 75.67; H, 9.84; N, 4.41.Found (percent): C, 75.48; H, 9.93; N, 4.30.

EXAMPLE 95 T rans-C-l- [2-(a,p-dintetlzoxyberzzyl eyclohexyl] piperidineA solution of 2 g. of hydrogen chloride in 15 ml. of methanol was addedto a solution of 0.8 g. (2.64 mmoles) of a-(p-methoxyphenyl) 2piperidinocyclohexanemethanol (trans-D isomer) in 40 ml. of methanol.The mixture was allowed to stand overnight. The resulting solution wasbasified with 20% aqueous sodium hydroxide solution. The methanol wasevaporated in vacuo, 25 ml. of water was added, and the product wasextracted with three portions of 25 ml. each of methylene chloride. Theextracts were combined, washed with saturated salt solu tion, dried overmagnesium sulfate and evaporated. The residue (0.8 g.) was dissolved in3% ether97% Skelly- 39 solve B hexanes and chromatographed over neutralalumina with the same solvent mixture. The column was eluted with tenportions of 100 ml. each of 3% ether-97% Skellysolve B hexanes and thefractions thus obtained were evaporated to give 0.351 g. of an oil,which was kept overnight at 10 C. and thereupon solidified. Thesolidified material was crystallized from methanol to give trans- C-1-[2(a,p dimethoxybenzyl)cyclohexylJpiperidine of melting point 78-79 0,identical with the compound of Example 93.

EXAMPLE 96 [2-(a-ethoxy-ponethoxybenzyl) cyclohexyl] piperidl'ne (cis-Aisomer) and the hydrochloride thereof A solution ofcis-A-u-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (30.3 g.; 0.1mole) in 250 ml. of ether was added during 45 minutes to a suspension offreshly prepared sodium amide (0.2 mole) in 1 l. of liquid ammonia. Themixture was stirred for 1 hour and then cooled in a Dry Ice-acetonebath. A solution of 31.2 g. (0.2 mole) of ethyl iodide in 100 ml. ofether was added dropwise over a period of 30 minutes, the mixture wasthen stirred in the cold for 1 hour and allowed to stir without coolingfor 2 hours. The solution was thereupon allowed to evaporate overnight.To the resulting product 500 ml. of water was added, and the mixture wasex tracted with 5 portions of 100 ml. each of methylene chloride. Theextracts were combined, washed with water, then with saturated saltsolution, dried by passage through anhydrous sodium sulfate andevaporated to give 30 g. of a yellow oil. A solution of this oil in 200ml. of petroleum ether (boiling range 3060 C.) was allowed tocrystallize overnight to give 15.8 g. (53% recovery) of starting alcoholas determined by mixed melting point (7880 C.). The filtrate wasevaporated, and the residue was chromatographed over 750 g. of neutralalumina. Elution with 6% ether-94% Skellysolve B hexanes (8 fractions of250 ml. each) gave 7.23 g. of oily cis-A-l- [Z-(OL ethoxy pmethoxybenzyl)cyclohexyl]piperidine which was 98.9% pure as determinedby vapor phase chromatography. Further elution with 25% ether-75%Skellysolve B hexanes (4 fractions of 250 ml. each) gave 0.546 g. of oilof one component; 50% ether-50% Skellysolve B hexanes (4 fractions of250 ml. each) gave 0.777 g. of oil and 2 fractions of 450 ml. each gave0.396 g. of oil. Total yield from the ethyl ether fractions was 30%.This oil did not crystallize. The oilycis-A-1-[2-(a-ethoxyp-methoxybenzyl)cyclohexyl]piperidine had thefollowing analysis:

Ultraviolet: A 226.5 (12,000); sh. 268, 276 (1,800); 284 (1,550).

Analysis.Calcd. for C H NO (percent): C, 76.09; H, 10.03; N, 4.23. Found(percent): C, 75.97; H, 10.10; N, 4.23.

The hydrochloride ofcis-A-l-[2-(a-ethoxy-p-methoxybenzyl)cyclohexylJpiperidine was preparedby treatment of an ethereal solution of the above oily base withethereal hydrogen chloride. Two recrystallizations from ethanol gavecolorless prisms of the hydrochloride of cis-A 1- 2-(41-ethoxy-p-methoxybenzyl) cyclohexyl] piperidine of melting point203204.5 C.

Ultraviolet: A 227 (11,900); 275 (1,500); 282 (1,300).

Analysis.Calcd. for C H NO -HCl (percent): C, 68.55; H, 9.31; Cl, 9.64;N, 3.81. Found (percent): C, 68.01; H, 9.42; Cl, 9.72; N, 3.59.

EXAMPLE 97 1-[2-(we!hoxy-p-nleth0xybenzyl)cyclohexyl]piperidine (cis-Bisomer) A solution of 26 g. of hydrogen chloride in 200 ml. of ethanolwas added to a solution ofcis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (12.1 g.; 0.03mole) in 1200 ml. of ethanol. After 20 hours, the mixture was filtered,and a precipitate collected of melting point 232-233 C. This materialwas unreacted starting material. The filtrate was cooled, basified withsodium hydroxide and evaporated to eliminate the ethanol. Thereafter 250ml. of water was added to the solution and the solution extracted withmethylene chloride to give 11.9 g. of a yellow oil. The yellow oil wasdissolved in 50 ml. of methylene chloride and chromatographed on 590 g.of neutral alumina using a solvent mixture of 12% ether 88% SkellysolveB hexanes (6 portions of 250 ml. each). The eluates were combined andevaporated to give 3.80 g. of thecis-B-l-[2-(a-ethoxy-p-methoxybenzyl)cyclohexyl]piperidine as an oil.

Ultraviolet: 227.5 (12,200); 268 (1,100); 276 (1,460); 233 (1,200).

Analysis.-Calcd. for C H NO (percent): C, 76.09; H, 10.03; N, 4.23.Found (percent): C, 76.14; H, 9.71; N, 4.31.

EXAMPLE '98 1-[2-(a,3,4,5-tetramethoxybenzyl)cyclohexyl] piperidine(cis-B isomer) A solution of 6 g. of hydrogen chloride in 50 ml. ofmethanol was added to a solution ofcis-A-a-(3,4,5-trimethoxyphenyl)-2-piperidinocyclohexanemethanolhydrochloride (2 g.; 0.005 mole) in 100 ml. of methanol, and theresulting solution was allowed to stand for 24 hours. The colorlesssolution was then evaporated to dryness at 40 C. The resulting solid wastriturated with ether and filtered, to give 2 g. of material meltingbetween 210 228 C. This material was crystallized from 20 ml. ofmethanol to give 0.7 g. of recovered starting material of melting point257-25 8 C. The filtrate was diluted with 1 ml. of ether to give 0.35 g.of additional starting material. Further dilution of the filtrate withml. of ether gave 0.2 g. of starting material; total recovery ofstarting material 62.5%. The remaining filtrate was evaporated todryness to give 0.7 g. of an amorphous solid. A solution of this solidin 20 ml. of water was basified with 20% aqueous sodium hydroxide. Themixture was extracted with three portions of 2 0 ml. each of methylenechloride. The extracts were combined, washed with water and saturatedsalt solution, then dried by passage through anhydrous sodium sulfate,and evaporated to give 0.53 g. (26.6% yield) of product. This productwas crystallized from methanol to give colorless needles ofCiS-B-1-[2-(oc,3,4,5- tetramethoxybenzyl)cyclohexyflpiperidine of m e 1tin g point 8990 C.

Ultraviolet: sh. 235 (7,600); Amax, 271 (868); sh. 280 (675).

Analysis.-Calcd for C H NO (percent): C, 69.99; H, 9.35; N, 3.71. Found(percent): C, 70.04; H, 9.47; N, 3.60.

EXABPLE 99 Cfs-A-l-[Z (a,pdimethoxyhenzyl)cyclohexyl]/zonallydro-IH-azepine and the hydrochlorideas methanol solvate A solution of 15.8 ml. of butyl lithium (0.03 mole)in hexane (1.9 M solution) was added dropwise during 5 minutes to asolution of cisA-cx-(p-methoxyphenyl)-2-(hexahydro-lH-azepin-l-yl)cyclohexanemethanol (9.5 g.; 0.03 mole) in ml.of tetrahydrofuran which had been previously purified by passage throughbasic alumina. The solution was stirred for a period of 35 minutes. Itwas then cooled to -70 C. and a solution of 4.36 g. (0.3 mole) of methyliodide in 30 ml. of tetrahydrofuran was added over a period of 30minutes. The mixture was stirred at 70 "C. for two hours and thenovernight (about 18 hours) at room temperature. It was evaporated todryness, 100 ml. of water was added and the product was extracted withthree portions of 100 ml. each of methylene chloride. The organicextract was washed with saturated salt solution, dried by passagethrough anhydrous sodium sulfate and evaporated, yielding 9.5 g. of

